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It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.

DOI： 10.1111/cas.15824

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CD8+ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8+ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8+ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8+ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8+ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8+ T cells to tumor sites, was substantially decreased in Utx KO CD8+ T cells. These findings suggest that Utx promotes CD8+ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.

DOI： 10.1111/cas.15814

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Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4+ T cells, CD8+ T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.

DOI： 10.1016/j.jid.2023.03.1667

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Language：English   Publisher：(一社)西日本泌尿器科学会  

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Myeloid differentiation primary response gene 88 (MyD88) is essential for microglial activation. Despite the significant role of microglia in regulating sleep homeostasis, the contribution of MyD88 to sleep is yet to be determined. To address this, we performed electroencephalographic and electromyographic recordings on MyD88-KO mice and wild-type mice to investigate their sleep/wake cycles. In the daytime, MyD88-KO mice exhibited prolonged wakefulness and shorter non-rapid eye movement sleep duration. Tail suspension and sucrose preference tests revealed that MyD88-KO mice displayed a depressive-like phenotype. We determined monoamines in the prefrontal cortex (PFC) using high-performance liquid chromatography and observed a decreased content of serotonin in the PFC of MyD88-KO mice. Flow cytometry revealed that CD11b, CD45, and F4/80 expressions were elevated at Zeitgeber time (ZT) 1 compared to at ZT13 only in wild-type mice. Furthermore, MFG-E8 and C1qB-tagged synapses were enhanced at ZT1 in the PFC of wild-type mice but not in MyD88-KO mice. Primary cultured microglia from MyD88-KO mice revealed decreased phagocytic ability. These findings indicate that genetic deletion of MyD88 induces insomnia and depressive behavior, at least in part, by affecting microglial homeostasis functions and lowering the serotonergic neuronal output.

DOI： 10.1016/j.jneuroim.2021.577794

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Glucocorticoids (GCs), immunosuppressive, and anti-inflammatory agents have various effects on T cells. However, the long-term influence of GCs on the T cell-mediated immune response remain to be elucidated. We demonstrated that the administration of GC during the TCR-mediated activation phase induced long-lasting suppression of glycolysis, even after the withdrawal of GC. The acquisition of the effector functions was inhibited, while the expression of PD-1 was increased in CD8 T cells activated in the presence of GC. Furthermore, adoptive transfer experiments revealed that GC-treated CD8 T cells reduced memory T cell formation and anti-tumor activity. These findings reveal that GCs have long-lasting influence on the T cell-mediated immune response via modulation of T cell metabolism.

DOI： 10.1016/j.bbrc.2021.12.050

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The pathogenesis of allergic contact dermatitis (ACD) requires the activation of Ag-specific T cells, including effector and regulatory T cells. The differentiation and function of these T cells is epigenetically regulated through DNA methylation and histone modifications. However, the roles of altered histone H3K27 methylation in T cells in the development of ACD remain unknown. Two types of histone H3K27 demethylases, Utx and Jmjd3, have been reported in mammals. To determine the role of the histone H3K27 demethylase expression of T cells in the development of ACD, we generated T cell-specific, Utx-deficient (Utx KO) mice or Jmjd3-deficient (Jmjd3 KO) mice. Unlike control mice, Utx KO mice had severer symptoms of ACD, whereas Jmjd3 KO mice showed symptoms identical to those in control mice. In Utx KO mice with ACD, the massive infiltration of myeloid cells, including neutrophils and dendritic cells, has been observed. In addition, the expression of proinflammatory cytokines in CD4+ T cells of the draining lymph nodes (LNs) and in CD8+ T cells of the skin was increased in Utx KO mice, whereas the ratio of Foxp3+ regulatory CD4+ T cells to Foxp3- conventional CD4+ T cells was decreased in both the draining LNs and the skin of Utx KO mice with ACD. Furthermore, Foxp3+ regulatory CD4+ T cells of Utx KO mice with ACD expressed a decreased level of CCR4 (a skin-tropic chemokine receptor) in comparison with control. Thus, in CD4+ T cells, Utx could potentially be involved in the regulation of the pathogenesis of ACD.

DOI： 10.4049/jimmunol.2001160

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<title>Abstract</title>Although the important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated. Furthermore, the influences of glycolytic failure on the T cell-dependent immune response in vivo remain unclear. We therefore assessed the role of glycolysis in the T cell-dependent immune response using T cell-specific <italic>Pgam1</italic>-deficient mice. Both CD8 and CD4 T cell-dependent immune responses were attenuated by Pgam1 deficiency. The helper T cell-dependent inflammation was ameliorated in <italic>Pgam1</italic>-deficient mice. Glycolysis augments the activation of mTOR complex 1 (mTORC1) and the T-cell receptor (TCR) signals. Glutamine acts as a metabolic hub in activated T cells, since the TCR-dependent increase in intracellular glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals. These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation and differentiation.

DOI： 10.1038/s42003-020-01122-w

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Other Link： http://www.nature.com/articles/s42003-020-01122-w

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Th2 cytokine such as IL-4, IL -5 and IL-13 are important therapeutic targets for Th2-type chronic inflammation. Several biologics targeting Th2 cytokine and its receptors are effective in clinical practice; however, the development of small-molecule compounds that inhibit Th2 cytokine productions is awaited. We found that an inhibitor for pyruvate dehydrogenase kinase (PDHK) suppresses the differentiation of IL-5/IL-13-producing Th2 cells. The expression of the Th2-related transcriptional factors Pparγ was decreased by treatment with inhibitor, whereas Gata3, a master regulator of Th2 cell differentiation, remained unchanged. The oxygen consumption rate was unaffected, whereas the level of farnesylated proteins was decreased by the PDHK inhibitor. Furthermore, the inhibitors for farnesyltransferase and hydroxymethylglutaryl-CoA reductase showed an inhibitory effect similar to that of the PDHK inhibitor. These results suggest that the mevalonate biosynthesis and subsequent protein prenylation may be novel therapeutic target for Th2 cell-dependent immune dysregulation, such as in allergic diseases.

DOI： 10.1016/j.bbrc.2020.08.009

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Prefractionation of complex mixtures of proteins derived from biological samples is indispensable for proteome analysis via top-down mass spectrometry (MS). Polyacrylamide gel electrophoresis (PAGE), which enables high-resolution protein separation based on molecular size, is a widely used technique in biochemical experiments and has the potential to be useful in sample fractionation for top-down MS analysis. However, the lack of a means to efficiently recover the separated proteins in-gel has always been a barrier to its use in sample prefractionation. In this study, we present a novel experimental workflow, called Passively Eluting Proteins from Polyacrylamide gels as Intact species for MS ("PEPPI-MS"), which allows top-down MS of PAGE-separated proteins. The optimization of Coomassie brilliant blue staining followed by the passive extraction step in the PEPPI-MS workflow enabled the efficient recovery of proteins, separated on commercial precast gels, from a wide range of molecular weight regions in under 10 min. Two-dimensional separation combining offline PEPPI-MS with online reversed-phase liquid chromatographic separation resulted in identification of over 1000 proteoforms recovered from the target region of the gel (≤50 kDa). Given the widespread availability and relatively low cost of traditional sodium dodecyl sulfate (SDS)-PAGE equipment, the PEPPI-MS workflow will be a powerful prefractionation strategy for top-down proteomics.

DOI： 10.1021/acs.jproteome.0c00303

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

The cancer immunotherapies based on adoptive T cell therapy (ACT) has been receiving increased attention by improvement of the curative effect. T cells for ACT are harvested from the patient, then activated and expanded in vitro. However, in vitro activated T cells frequently show dysfunction after adoptive transfer, such as the exhaustion and the senescence. The exhausted/senescent T cells reduces the effector functions and fails to eliminate tumor cells. Therefore, the development of the culture method avoiding a T cell exhaustion and senescence. Recent findings reveal the dramatic changes of the metabolic status in T cells during T-cell receptor (TCR)-mediated activation. We recently reported that the activation status of glutami-nolysis during TCR-stimulation determines the activated CD8T cell fate. We considered that the therapeutic effect of ACT will be improved by the modulation of glutaminolysis. We demonstrated that the CD8 T cell exhaustion and/or senescence is prevented and the antitumor activity of adoptively transferred CD8T cells is reinforced by the glutamine restriction during in vitro culture. The adoptively transferred CD8 T cells cultured under glutamine-restricted conditions shows higher infiltration in the tumor sites than that of CD8 T cells cultured under normal conditions. The expression of inhibitory receptors, such as PD-1 is decreased in tumor-infiltrating CD8 T cells cultured under glutamine-restricted conditions. Furthermore, the restriction of glutamine during CD8T cell activation in vitro drives memory T cell development after adoptive transfer. The effect of glutamine restriction is antagonized by α-ketoglutarate, a metabolite of glutaminolysis. Thus, our recent findings suggest that the glutamine-restricted culture of CD8 T cells in vitro will improve the efficacy of CD8 T cell-based ACT.

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AIM/INTRODUCTION: Insulin administration was found to trigger type 1 diabetes in six Japanese type 2 diabetes patients with type 1 diabetes high-risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype. The objective of the present study was to assess the contribution of non-human leukocyte antigen single-nucleotide polymorphisms (SNPs) to the risk of developing insulin-triggered type 1 diabetes. MATERIALS AND METHODS: We genotyped 13 type 1 diabetes susceptible SNPs in six patients and compared them with those in Japanese controls (Hap Map3-JPT). The SNPs that showed statistically significant results were further analyzed using non-diabetic control participants and participants with type 2 diabetes at the Ehime University Hospital. RESULTS: The risk allele frequency of BACH2 rs3757247 in the six patients was significantly more frequent than that in 86 Japanese controls (P = 0.038). No significant difference in the allele frequency was observed in the other SNPs. This result was confirmed by the findings that the risk allele frequency of BACH2 in the six patients was significantly higher than that in the non-diabetic control participants (n = 179) and type 2 diabetes with or without insulin treatment (n = 154 or n = 152; P = 0.035, 0.034 or 0.037, respectively). Despite being statistically not significant, the six patients were all homozygous for the CLEC16A rs12708716 risk allele and five were homozygous for the CLEC16A rs2903692 risk allele. CONCLUSIONS: In addition to type 1 diabetes high-risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype, the possibility that the risk variants of BACH2 and CLEC16A could contribute to the development of insulin-triggered type 1 diabetes cannot be excluded.

DOI： 10.1111/jdi.13057

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DOI： 10.1038/s41598-019-53856-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association of Immunologists  

The basic leucine zipper (bZIP) transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells, but not IL-9 or IL-17 in the reciprocal subset. The mechanism for this restricted activity is unclear. In this report, we define BATF binding partners that contribute to Th subset–specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. Using primary mouse T cell culture, we observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest, but significant, increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, cotransduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cells. Taken together, our results reveal that JunB, c-Jun, and Bach2 cooperate with BATF to contribute to the specificity of BATF-dependent cytokine induction in Th subsets.

DOI： 10.4049/jimmunol.1900128

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DOI： 10.4049/jimmunol.1801083

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DOI： 10.1111/cas.13827

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While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in menin-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by menin deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in menin-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.

DOI： 10.1038/s41467-018-05854-6

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DOI： 10.1093/intimm/dxy020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

T helper type 2 (Th2) cytokines, IL-4 and IL-13, attenuate the expression of genes that regulate epidermal cellular structures and the barrier function at the terminal stage of keratinocyte differentiation. However, whether these Th2 cytokines act at earlier stages remains unknown. We investigated the roles of cytokines in expression levels of mRNAs and/or proteins in primary mouse keratinocytes and human keratinocyte HaCaT cells at earlier stages. We showed that IL-4 downregulated the expression levels of Krt1, Krt10, Dsg1, and Dsc1 via IL-4Rα- and signal transducer and activator of transcription factor 6 (STAT6)-dependent mechanisms in differentiating mouse keratinocytes at early stages. As the expression levels of keratin-1 and -10 in the keratinocytes transiently expressing an active form of STAT6 were not downregulated, STAT6 and other IL-4-induced molecules may synergistically regulate this expression. The restoration of the downregulated expression levels of Krt1 and Krt10 induced by IL-4 with the MEK (mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase) inhibitor U0126 indicated the involvement of the p44/42 MAPK signaling pathway in the attenuated expression. IL-13 also downregulated the expression of the four genes. Furthermore, IL-4 or IL-13 caused the downregulation of these genes in HaCaT cells and promoted the fragmentation of cell sheets with mechanical stress. Our results showed that IL-4 or IL-13 acted on differentiating keratinocytes in vitro at early stages to attenuate the gene expression.

DOI： 10.1038/jid.2013.503

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DOI： 10.1016/j.jid.2017.12.014

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Language：English   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN- released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.

DOI： 10.1074/jbc.M117.808535

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

IL-17 is known to be a cytokine mainly secreted from T-h 17 cells, which well associate with autoimmune inflammatory responses. In the generation of T-h 17 cells, RORc and RORa have pivotal roles in controlling the transcription of Il17. We speculated additional regulation in Il17a transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for Il17a promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase Il17a promoter activity in a T-cell line and to promote T-h 17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein, which is reported to directly regulate expression of Il17a and Rorgt at the transcriptional level. In the absence of HIF-1 alpha, both ubiquitin ligases had little effect on T-h 17 ]cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote T-h 17 cell differentiation through maintaining the stability of HIF-1 alpha protein.

DOI： 10.1093/intimm/dxx014

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Publishing type：Research paper (scientific journal)   Publisher：OMICS Publishing Group  

DOI： 10.4172/2155-6121.1000267

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8(+) T cells remains unclear. We generated Menin(flox/flox) CD4-Cre (Menin-KO) mice by crossing Menin(flox/flox) mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8(+) T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8(+) T cells. Menin deficiency resulted in an impaired primary immune response by CD8+ T cells. On day 7, there were fewer Menin-KO OVA-specific CD8(+) T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8(+) T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8(+) T cell-intrinsic effect. Menin-KO OT-1 Tg CD8(+) T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8(+) T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8(+) T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8(+) T cells to infection.

DOI： 10.4049/jimmunol.1502295

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although Bach2 has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we find that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf-Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2-Batf interactions are required to prevent an excessive Th2 response.

DOI： 10.1038/ncomms12596

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background:Carbonic anhydrase I (CA I), a major cecal bacterial antigen, improves inflammatory bowel disease (IBD) symptoms in a murine model. The aim of this study was to identify the responsible epitope region within the CA I protein and evaluate its effect on inflammation using a murine IBD model.Methods:Candidate peptides within the CA I protein sequence that interact with major histocompatibility complex class II were chosen and their immune responses were evaluated using mesentery lymph nodes (MLNs) from a CD4(+)CD25(-) T-cell transfer murine colitis model. Mice were treated with regulatory dendritic cells (Reg-DCs)-pulsed CA I peptide. We assessed their clinical signs, histopathology, induction of cytokines and transcription factors, and generation of CD103(+)CD11c(+) dendritic cells and regulatory T cells (Tregs).Results:We identified 4 candidate epitope peptides of CA I. Among these, Reg-DCs pulsed with CA I 58-73 peptide (Reg-DCsCA I 58-73) alone ameliorated colitis. Reg-DCsCA I 58-73-treated mice showed higher mRNA expression levels of forkhead box protein 3, aldehyde dehydrogenase family 1a2, transforming growth factor-, and interleukin (Il)10, when compared with lower mRNA expression of retinoic acid-related orphan receptor gamma and Il17a in MLNs. Compared with control mice, these mice also showed higher numbers of Foxp3(+)CD4(+)CD25(+) Tregs and CD103(+)CD11c(+) dendritic cells in MLNs and colon. Administration of Reg-DCsCA I 58-73 induced antigen-specific Tregs in MLNs of colitic mice.Conclusions:CA I 58-73 peptide induces antigen-specific therapeutic effect in a murine IBD model using Reg-DCs, indicating that CA I 58-73 is a candidate epitope for IBD immunotherapy.

DOI： 10.1097/MIB.0000000000000781

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Gfi1 plays an important role in the development and maintenance of many hematopoietic linage cells. However, the impact of Gfi1-deficiency on the iNKT cell differentiation remains unclear. We herein demonstrate a critical role of Gfi1 in regulating the development of iNKT cell subsets. In the thymus of T cell-specific Gfi1-deficient mice, iNKT cells normally developed up to stage 2, while the number of stage 3 NK1.1(pos) iNKT cells was significantly reduced. Furthermore, CD4(pos) iNKT cells were selectively reduced in the peripheral organs of T cell-specific Gfi1-deficient mice. The alpha-GalCer-dependent production of IFN-gamma and Th2 cytokines, but not IL-17A, was severely reduced in T cell-specific Gfi1-deficient mice. In addition, a reduction of the alpha-GalCer-induced anti-tumor activity was observed in Gfi1-deficient mice. These findings demonstrate the important role of Gfi1 in regulating the development and function of NKT1- and NKT2-type iNKT cell subsets.

DOI： 10.1371/journal.pone.0157395

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1-deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12-and interferon-gamma-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response.

DOI： 10.1111/imm.12580

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Other Link： http://search.jamas.or.jp/link/ui/2015290722

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Infection with certain pathogens induces a shift of the T-h subset balance to a T(h)1 dominant state. This, in turn, results in the suppression of T(h)2 responses. We focused on the involvement of interferon regulatory factor-1 (IRF-1) in the suppression of T(h)2 cells during Listeria infection. We found that the inhibition of IL-4 production by T(h)2 cells is mediated by a soluble factor (LmSN) produced by Listeria-infected antigen-presenting cells. The inhibition is not observed with T cells from Irf1 gene-targeted mice. IRF-1 suppresses transcription of the Il4 gene in T(h)2 cells. Under the influence of the LmSN, IRF-1 binds to the 3 ' untranslated region (UTR) region of the Il4 gene and down-regulates Il4 gene transcription. Finally, we identified IL-1 alpha and IL-1 beta as the mediator of the LmSN activity. Signaling through IL-1R induces the stabilization and/or nuclear translocation of IRF-1. We propose that IRF-1 functions to induce the T-cell subset shift via a novel mechanism. Under the influence of IL-1, IRF-1 translocates into the nucleus and acts on the 3 ' UTR region of the Il4 gene, thus inhibiting its transcription in T(h)2 cells. As a result, the immune system shifts predominantly to a T(h)1 response during Listeria infection, resulting in effective protection of the host.

DOI： 10.1093/intimm/dxu092

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Language：English   Publisher：(NPO)日本免疫学会  

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Stat3 signaling is essential for the induction of ROR gamma t and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for ROR gamma t expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell-specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4(+) T cells but not in ROR gamma t-deficient CD4(+) T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of ROR gamma t. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of ROR gamma t in CD4(+) T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of ROR gamma t as downstream targets of Stat3.

DOI： 10.1084/jem.20130791

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Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.

DOI： 10.1371/journal.pone.0100359

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

T helper type 2 (Th2) cytokines, IL-4 and IL-13, attenuate the expression of genes that regulate epidermal cellular structures and the barrier function at the terminal stage of keratinocyte differentiation. However, whether these Th2 cytokines act at earlier stages remains unknown. We investigated the roles of cytokines in expression levels of mRNAs and/or proteins in primary mouse keratinocytes and human keratinocyte HaCaT cells at earlier stages. We showed that IL-4 downregulated the expression levels of Krt1, Krt10, Dsg1, and Dsc1 via IL-4R alpha- and signal transducer and activator of transcription factor 6 (STAT6)-dependent mechanisms in differentiating mouse keratinocytes at early stages. As the expression levels of keratin-1 and -10 in the keratinocytes transiently expressing an active form of STAT6 were not downregulated, STAT6 and other IL-4-induced molecules may synergistically regulate this expression. The restoration of the downregulated expression levels of Krt1 and Krt10 induced by IL-4 with the MEK (mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase kinase) inhibitor U0126 indicated the involvement of the p44/42 MAPK signaling pathway in the attenuated expression. IL-13 also downregulated the expression of the four genes. Furthermore, IL-4 or IL-13 caused the downregulation of these genes in HaCaT cells and promoted the fragmentation of cell sheets with mechanical stress. Our results showed that IL-4 or IL-13 acted on differentiating keratinocytes in vitro at early stages to attenuate the gene expression.

DOI： 10.1038/jid.2013.503

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Although CD4 T-cell senescence plays an important role in immunosenescence, the mechanism behind this process remains unclear. Here we show that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, which is accompanied by the senescence-associated secretory phenotype after antigenic stimulation and dysregulated cytokine production. Menin is required for the expansion and survival of antigen-stimulated CD4 T cells in vivo and acts by targeting Bach2, which is known to regulate immune homeostasis and cytokine production. Menin binds to the Bach2 locus and controls its expression through maintenance of histone acetylation. Menin binding at the Bach2 locus and the Bach2 expression are decreased in the senescent CD4 T cells. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T-cell senescence and cytokine homeostasis, thus indicating the involvement of this pathway in the inhibition of immunosenescence.

DOI： 10.1038/ncomms4555

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

The consumption of probiotics by pregnant and lactating women may prevent the onset of allergic disorders in their children by increasing the concentrations of immunoactive agents such as cytokines in breast milk. Prebiotics such as fructo-oligosaccharides (FOS) increase the number of beneficial organisms such as bifidobacteria. Thus, prebiotics may have an effect similar to that of probiotics. The objective of the present study was to carry out a comprehensive analysis of mRNA expression in human milk cells to identify changes in the concentrations of cytokines in breast milk after the consumption of FOS (4gx2 times/d) by pregnant and lactating women. The microarray analysis of human milk cells demonstrated that the expression levels of five genes in colostrum samples and fourteen genes in 1-month breast milk samples differed more than 3-fold between the FOS and control groups (sucrose group). The mRNA expression level of IL-27, a cytokine associated with immunoregulatory function, was significantly higher in 1-month breast milk samples obtained from the FOS group than in those obtained from the control group. In addition, the protein concentrations of IL-27 in colostrum and 1-month breast milk samples were significantly higher in the FOS group than in the control group. In conclusion, the consumption of FOS by pregnant and lactating women increases the production of IL-27 in breast milk. Future studies will address the association of this phenomenon with the onset of allergic disorders in children.

DOI： 10.1017/S0007114513003036

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There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan
however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1+/- mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases. © 2013 Nojima et al.

DOI： 10.1371/journal.pone.0069178

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IL-5 is a key cytokine that plays an important role in the development of pathological conditions in allergic inflammation. Identifying strategies to inhibit IL-5 production is important in order to establish new therapies for treating allergic inflammation. We found that SH-2251, a novel thioamide-related small compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the induction of active histone marks at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II, and following expression of the Th2 cell-specific intergenic transcripts around the Il5 gene locus was also inhibited. Furthermore, Th2 cell-dependent airway inflammation in mice was suppressed by the oral administration of SH-2251. Gfi1, a transcriptional repressor, was identified as a downstream target molecule of SH-2251 using a DNA microarray analysis. The Gfi1 expression dramatically decreased in SH-2251-treated Th2 cells, and the SH-2251-mediated inhibition of IL-5-producing Th2 cell differentiation was restored by transduction of Gfi1. Therefore, our study unearthed SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits active histone marks at the Il5 gene locus. © 2013 Suzuki et al.

DOI： 10.1371/journal.pone.0061785

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It has been proposed that sustained ICOS expression in chronic inflammatory immune conditions, such as autoimmunity and allergy, contributes to symptom exacerbation. Therefore modulation of ICOS gene expression could be a potential therapeutic strategy for such immune diseases. However, the precise molecular mechanisms controlling ICOS gene expression remain poorly understood. In this study, we explored transcription factors involving in ICOS gene expression and examined their roles in a physiological situation. Microarray analysis revealed that one AP-1 molecule, Fos-related antigen-2 (Fra2), was highly correlated with ICOS expression. Ectopic expression of Fra2 and other AP-1 molecules upregulated ICOS expression on T cells. We identified an AP-1-responsive site (AP1-RE) within the ICOS promoter region and demonstrated AP-1 actually binds to AP1-RE upon TCR/CD28 stimulation. Meanwhile, we found several cytokines could upregulate ICOS expression on both naive and effector T cells in a manner independent of TCR/CD28 stimulation. These cytokine stimuli induced AP-1 binding to AP1-RE. Together, our results indicate AP-1 transcription factors are involved in ICOS gene expression downstream of both TCR/CD28 signaling and cytokine receptor signaling, and suggest AP-1 activation via cytokine receptor signaling may be one of the mechanisms maintaining high level ICOS expression in chronic inflammatory immune responses.

DOI： 10.1002/eji.201141897

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IL-4 plays an important role in the induction of Th2 and Th9 cells, as well as in the inhibition of Th1 cell generation. We show that a combination of IL-4 and TGF-beta augments the development of Th1 cells that express CD103 (CD103(+) Th1 cells) if IFN-gamma is present. The T-box-containing transcription factor eomesodermin (Eomes) is preferentially expressed in CD103(+) Th1 cells and is involved in IFN-gamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFN-gamma gene loci. TGF-beta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6-signaling pathway. IFN-gamma-producing CD103(+) Th1 cells are detected in the intraepithelial lymphocytes of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. To our knowledge, these results represent the first molecular mechanism of IL-4/TGF-beta-dependent augmentation of Th1 cell generation and raise the possibility that IL-4 and TGF-beta simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. The Journal of Immunology, 2012, 188: 4846-4857.

DOI： 10.4049/jimmunol.1103799

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DOI： 10.1038/ni.2362

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The regulation of memory CD4(+) helper T (Th) cell function, such as polarized cytokine production, remains unclear. Here we show that memory T helper 2 (Th2) cells are divided into four subpopulations by CD62L and CXCR3 expression. All four subpopulations produced interleukin-4 (IL-4) and IL-13, whereas only the CD62L(lo)CXCR3(lo) population produced IL-5 accompanied by increased H3-K4 methylation at the 115 gene locus. The transcription factor Eomesodermin (encoded by Eomes) was highly expressed in memory Th2 cells, whereas its expression was selectively downregulated in the IL-5-producing cells. 115 expression was enhanced in Eomes-deficient cells, and Eomesodermin was shown to interact with the transcription factor GATA3, preventing GATA3 binding to the 115 promoter. Memory Th2 cell-dependent airway inflammation was attenuated in the absence of the CD62L(lo)CXCR3(lo) population but was enhanced by Eomes-deficient memory Th2 cells. Thus, IL-5 production in memory Th2 cells is regulated by Eomesodermin via the inhibition of GATA3 activity.

DOI： 10.1016/j.immuni.2011.08.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Functionally polarized helper T cells (Th cells) play crucial roles in the induction of tumor immunity. There is considerable knowledge about the contributions of IFN-producing Th1 cells that supports the role of cytotoxic cluster of differentiation (CD8) T cells and natural killer (NK) cells, but much less is known about how IL-4-producing Th2 cells contribute to tumor immunity. In this study, we investigated the cellular and molecular mechanisms employed by memory Th2 cells in sustaining tumor immunity by using a mouse model system wherein ovalbumin (OVA) is used as a specific tumor antigen. In this model, we found that OVA-specific memory Th2 cells exerted potent and long-lasting antitumor effects against NK-sensitive OVA-expressing tumor cells, wherein antitumor effects were mediated by NK cells. Specifically, NK cell cytotoxic activity and expression of perforin and granzyme B were dramatically enhanced by the activation of memory Th2 cells. Interleukin 4 (IL-4) produced by memory Th2 cells in vivo was critical for the antitumor effects of the NK cells, which IL-4 directly stimulated to induce their perforin-and granzyme-B-dependent cytotoxic activity. Our findings show that memory Th2 cells can induce potent antitumor immunity through IL-4-induced activation of NK cells, suggesting potential applications in cellular therapy for cancer patients. Cancer Res; 71(14); 4790-8. (C) 2011 AACR.

DOI： 10.1158/0008-5472.CAN-10-1572

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Repressor of GATA (ROG) inhibits Th2 cell differentiation and allergic airway inflammation in the lung. To determine the role of ROG in the pathogenesis of contact hypersensitivity (CHS), a hapten-induced mouse model of CHS using ROG Tg and ROG-deficient (ROG(-/-)) was used. ROG Tg mice showed little ear swelling, while ROG(-/-) mice showed enhanced ear swelling in comparison to wild type mice. Interstitial edema and mast cell degranulation at the local inflammation sites were mild in ROG Tg mice and exacerbated in ROG(-/-) mice. In addition, the serum total IgE and hapten-specific IgG1 levels were increased in ROG(-/-) mice. Adoptive transfer of ROG(-/-) CD4(+) T cells exacerbated CHS in wild type mice, while transfer of ROG Tg CD4(+) T cells resulted in the attenuation of CHS. These results indicate ROG negatively regulates the induction of CHS by controlling the CD4(+) T cell-mediated allergic responses, including IgE generation and mast cell degranulation. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2011.02.009

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Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, alpha-galactosylceramide (alpha GalCer). A phase I-II clinical study of alpha GalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-gamma (IFN-gamma) production (&gt; two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56+ cells and CD56-CD3+ T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-gamma production after alpha GalCer-pulsed DC treatment. (Cancer Sci 2010; 101: 2333-2340).

DOI： 10.1111/j.1349-7006.2010.01696.x

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Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I-II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (&gt
two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56+ cells and CD56-CD3+ T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment. (Cancer Sci 2010
101: 2333-2340) © 2010 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2010.01696.x

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In the periphery, upon antigen recognition by alpha beta TCR, naive CD4 T cells undergo functional differentiation and acquire the ability to produce a specific set of cytokines. At least four Th cell subsets, i.e., Th1, Th2, Th17 and iTreg cells have so far been identified and the differentiation of each subset is driven by distinct cytokine sets. Antigen recognition by TCR and the activation of the TCR-mediated signaling pathways that follows, however, are most critical for initiating Th cell differentiation. This review focuses on the TCR signal strength and the TCR-mediated signaling pathways that control the differentiation into these four Th cell subsets. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.smim.2010.04.010

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DOI： 10.1084/jem.20100760

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DOI： 10.4049/jimmunol.0903426

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Recently, it was reported that the expression of Runt-related transcription factor 3 (Runx3) is up-regulated in CD4(+) helper T cells during Th1 cell differentiation, and that Runx3 functions in a positive feed-forward manner with the T-box family transcription factor, T-bet, which is a master regulator of Th1 cell differentiation. The relative expression levels of IFN-gamma and IL-4 are also regulated by the Th2-associated transcription factor, GATA3. Here, we demonstrate that Runx3 was induced. in Th2 as well as Th1 cells and that Runx3 interacted with GATA3 and attenuated GATA3 transcriptional activity. Ectopic expression of Runx3 in vitro in cultured cells or transgenic expression of Runx3 in mice accelerated CD4(+) cells to a Th1-biased population or down-modulated Th2 responses, in part by neutralizing GATA3. Our results suggest that the balance of Runx3 and GATA3 is one factor that influences the manifestation of CD4(+) cells as the Th1 or Th2 phenotypes. The Journal of Immunology, 2009,183: 7817-7824.

DOI： 10.4049/jimmunol.0802527

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DOI： 10.4049/jimmunol.0900646

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BEGELL HOUSE INC  

Allergic asthma is an airway inflammatory disease characterized by chronically increased expression of multiple inflammatory proteins, including cytokines, chemokines, adhesion molecules, enzymes, and receptors. Several transcription factors are known to play a crucial role in the pathogenesis of chronic inflammatory diseases such as asthma, including signal transducer and activator of transcription factors, nuclear factor-kappaB, nuclear factor of activated T cells, activator protein-1 family proteins, and Th2 cell-related transcription factors including GATA3, JunB, and c-Maf Modulation of the activity of certain transcription factors has been shown to result in the inhibition of inflammation during asthma. Terefore, both agonists and inhibitors of transcription factors may be potential tools for the treatment of asthma. In this review, we summarize the current knowledge of the role of well-established transcription factors in asthma.

DOI： 10.1615/CritRevImmunol.v27.i6.40

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Language：English   Publisher：The Biophysical Society of Japan General Incorporated Association  

DOI： 10.2142/biophys.46.S137_2

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Th2 cells are generated from naive CD4 T cells upon T cell receptor (TCR) recognition of antigen and IL-4 stimulation and play crucial roles in humoral immunity against infectious microorganisms and the pathogenesis of allergic and autoimmune diseases. A tyrosine phosphatase, SHP-1, that contains src homology 2 (SH2) domains is recognized as a negative regulator for various intracellular signaling molecules, including those downstream of the TCR and the IL-4 receptor. Here we assessed the role of SHP-1 in Th1/Th2 cell differentiation and in the development of Th2-dependent allergic airway inflammation by using a natural SHP-1 mutant, the motbeaten mouse. CD4 T cells appear to develop normally in the heterozygous motheaten (me/+) thymus even though they express decreased amounts of SHP-1 (about one-third the level of wild-type thymus). The me/+ naive splenic CD4 T cells showed enhanced activation by IL-4 receptor-mediated signaling but only marginal enhancement of TCR-mediated signaling. Interestingly, the generation of Th2 cells was increased and specific cytokine production of mast cells was enhanced in me/+ mice. In an OVA-induced allergic airway inflammation model, eosinophilic inflammation, mucus hyperproduction, and airway hyperresponsiveness were enhanced in me/+ mice. Thus, SHP-1 may have a role as a negative regulator in the development of allergic responses, such as allergic asthma.

DOI： 10.1172/JCI200315719

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T cells play a central role in acquired immunity by recognizing foreign antigens through T-cell antigen receptor (TCR). Upon antigen recognition, two major downstream signaling pathways are activated. One is the calcium/calcineurin pathway and the other is the Ras-ERK MAPK cascade. T-cell repertoire is established in the thymus by TCR-dependent positive and negative selection. Negative selection of autoreactive thymocytes occurs in the developing CD4⁺CD8⁺ stage and is mediated by calcium-dependent apoptotic cell death. Developing CD4⁺CD8⁺ thymocytes are known to be highly susceptible to apoptotic cell death. We reported that the activation of the calcium/calcineurin pathway is required for positive selection but not negative selection. We established a video-imaging system that is able to analyze the intracellular calcium ion concentration ([Ca²⁺]_i) induced by cell-cell interaction. We found that the increased [Ca²⁺]_i in thymocytes was sustained for more than 5 min, while in mature T cells in the periphery it decreased significantly within a minute. These results suggest that calcium mobilization induced by TCR recognition of antigen in T cells is developmentally regulated. These qualitatively distinct calcium responses may reflect a difference in susceptibility to calcium-dependent apoptotic cell death between thymocytes and mature T cells.

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DOI： 10.1073/pnas.97.2.740

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Vα14 NKT cells express an invariant antigen receptor encoded by Vα14 and Jα281 gene segments as well as natural killer (NK) markers, including NK1.1. Here, we describe a precursor population of NKT cells (pre-NKT) that expresses NK1.1, T cell antigen receptor β, pTα, and RAG1/2 but not Vα14 and surface CD3ε. Such pre-NKT cells were differentiated successfully in vitro into mature CD3ε+ Vα14+ NKT cells by IL-15 and granulocyte/macrophage colony-stimulating factor (GM-CSF) in conjunction with stroma cells. Interestingly, only GM-CSF without stroma cells induced the Vα14-Jα281 gene rearrangement in the pre-NKT cells. This also was confirmed by the findings that the number of mature Vα14 NKT cells and the frequency of Vα14-Jα281 rearrangements were decreased significantly in the mice lacking a GM-CSF receptor component, common β-chain. These results suggest a crucial role of GM-CSF in the development of Vα14 NKT cells in vivo.

DOI： 10.1073/pnas.96.13.7439

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DOI： 10.1073/pnas.96.3.1024

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DOI： 10.1093/intimm/10.2.147

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A single intravenous injection of concanavalin A (Con A) induces T-cell activation-associated inflammatory injury selectively in the liver. This study investigated the strain difference in the development of Con A-induced hepatic injury. Normal C57BL/6 and BALB/c spleen cells produced comparable levels of T-cell-derived lymphokines (interferon gamma [IFN-γ], tumor necrosis factor α [TNF-α], and interleukin-2 [IL-2]) following in vitro stimulation with Con A. A single intravenous injection of Con A to C57BL/6 mice induced the plasma levels of TNF-α and IL-2 comparable with or slightly higher than those observed in BALB/c mice, whereas the same treatment resulted in an apparently lower level of IFN-γ production in C57BL/6 mice. RNA from livers of Con A-treated C57BL/6 mice exhibited lower levels of IFN- γ mRNA than RNA of BALB/c livers. Unexpectedly, a dramatic difference in the severity of hepatic injury was observed between C57BL/6 and BALB/c. Namely, the peak alanine transaminase (ALT) level was more than 15,000 U/L and inducible as early as 8 hours after injection of 0.2 mg Con A per mouse in the C57BL/6 strain, whereas the peak was approximately 3,000 U/L and induced as late as 24 hours after Con A injection in the BALB/c strain. The increase in plasma ALT levels was limited to less than 10% by injection of anti-IFN- γ monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of IFN-γ exhibited higher IFN-γ responsiveness as exemplified by the intrahepatic expression of an IFN-γ-inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN- γ produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN-γ-dependent hepatic injury.

DOI： 10.1002/hep.510270227

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DOI： 10.1093/intimm/10.5.577

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The present study investigates the role of non-T cell-derived IL-4 in IgE production. It is well known that IL-4 is generally produced by T cells and induces IgE production. We have demonstrated that non-T cells also produce IL-4 in vivo by injection with Ag following passive sensitization of mice with IgE. In contrast to its known potent immunosuppressive effects on T cells, FK506 only partially inhibited IL-4 produced by non-T cells; therefore, FK506 was found to be a useful tool for identifying a cell source of IL-4 production. We used this observation to examine the role of non-T cell-derived IL-4 in IgE production. The production of a high titer of IgE was induced by priming BALB/c mice with Ascaris suum extract and further enhanced by secondary immunization. The IgE production in this model was dependent on IL-4, since both primary and secondary IgE production were completely suppressed by injection with anti-IL-4 Ab. Although primary IgE production was completely inhibited by FK506, secondary IgE production was not inhibited. Furthermore, IL-4 induction in plasma was only partially inhibited by FK506 when the A. suum extract-primed mice were resensitized with Ag. These results indicate that IL-4 produced by non-T cells plays a crucial role in secondary IgE production.

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A single intravenous injection of concanavalin A (Con A) induces T-cell activation and an acute hepatitis in mice. This study investigated the role of interferon gamma (IFN-γ) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin-2 (IL-2), and IFN-γ, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN-γ levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN- γ levels were detected for a more prolonged period. Passive immunization with anti-IFN-γ monoclonal antibody (MAb) conferred a dose-dependent protection against liver injury in this model. This protection was observed when anti-IFN-γ MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A-induced hepatitis was also induced by administration of rIL-6 before Con A injection. rIL-6 treatment induced significant albeit incomplete inhibition of IFN-γ and TNF production, whereas this regimen did not affect IL-2 production. Despite striking protective effects of rIL-6 or anti-IFN-γ MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL-6 or anti-IFN-γ MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN-γ plays a critical role in the development of Con A-induced acute hepatitis and suggest that IL-6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN-γ.

DOI： 10.1053/jhep.1996.v23.pm0008675184

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We examined the effect of dextran sulfate on guinea pig tracheal vascular permeability. I.v. injection of dextran sulfate (10-100 mg/kg) with captopril (1 mg/kg) induced guinea pig tracheal plasma extravasation. The i.v. administration of bradykinin (0.8-8 μg/kg) with captopril (1 mg/kg) also induced plasma extravasation. Bradykinin B2 antagonists, D-Arg[Hyp3-Thi5-D-Tic7-Tic8]-bradykinin (NPC 16731) and D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin (Hoe 140), reduced both dextran sulfate (32 mg/kg)- and bradykinin (2.5 μg/kg)-induced tracheal plasma extravasation in a dose-dependent manner. However, a cyclooxygenase inhibitor, indomethacin (1mg/kg), and a neurokinin antagonist, {N-[N2-[N-[N-[N-[2,3didehydro-N-methyl-N-[N-[3-(2-p entyiphenyl)-propionyl]-L-threonylltyrosyl-L-leucynyl] -D-phenylalanyl]-L-allo-threonyl]-L-asparaginyl]-L-serine-v-lactone} (FK224) (1mg/kg), had no effect on tracheal plasma extravasation induced by dextran sulfate and bradykinin. Dextran sulfate (32 mg/kg) with captopril (1 mg/kg) greatly increased the bradykinin level in guinea pig plasma. This evidence suggests that dextran sulfate releases bradykinin in guinea pig plasma and causes guinea pig tracheal plasma extravasation via the activation of bradykinin B2-receptors.

DOI： 10.1254/jjp.72.217

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We examined the effects of novel tachykinin antagonists, FR 113680 (Nα-[Nα-(Nα-acetyl-L-threonyl)-N1-formyl-D-tryptophyl]-N-methyl-N-phenylmethyl-L-[phenylalaninamide) and FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-phenthylphenyl)-propionyl]-L-threonyl]-tyrosyl]-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-asparaginyl]-L-serinev-lactone) on rat tracheal plasma extravasation induced by cigarette smoke. Intravenous injection of FK 224 (0.032-3.2 mg kg1) inhibited rat tracheal plasma extravastion induced by cigarette smoke and capsaicin. FR 113680 (32 mg kg-1 i.v.) also significantly inhibited cigarette smoke-induced plasma extravasation, whereas D-chlorpheniramine maleate, FPL 55712, atropine sulfate and indomethacin had no effect. Tracheal plasma extravasation induced by substance P (SP) and neurokinin A (NKA), but not histamine, was also reduced by intravenous administration of FR 113680 and FK 224. These findings suggest that cigarette smoke stimulates primary afferent sensory nerves, releases tachykinins and evokes plasma extravasation in rat trachea. © 1992.

DOI： 10.1016/0014-2999(92)94810-I

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DOI： 10.14952/SEIKAGAKU.2015.870342

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DOI： 10.3388/jspaci.26.30

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DOI： 10.15036/arerugi.61.1532_2

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DOI： 10.1271/kagakutoseibutsu.48.810

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DOI： 10.15036/arerugi.59.1344_3

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

The maintenance of memory CD4 T cells is crucial for the establishment of immunological memory. The Polycomb (PcG) and Trithorax group (TrxG) genes control key developmental regulators such as the homeobox genes, and these two antagonize each other in the same developmental processes. Recently, PcG gene Bmi1 has been found to control memory Th1/Th2 cell survival and TrxG gene MLL is to control the maintenance of memory Th2 cell function selectively. Therefore, in memory CD4 T cells, PcG and TrxG genes appear to control distinct processes in a distinct manner, which indicates a novel regulatory feature of the PcG/TrxG genes. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.smim.2009.02.001

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Background: Studies of human asthma and of animal models of allergic inflammation/asthma highlight a crucial role for T(H)2 cells in the pathogenesis of allergic asthma. Repressor of GATA (ROG) is a POZ (BTB) domain-containing Kruppel-type zinc finger family (or POK family) repressor. A repressive function to GATA3, a master transcription factor for T(H)2 cell differentiation, is indicated.
Objective: The aim of this study was to clarify the regulatory roles of ROG in the pathogenesis of T(H)2-driven allergic diseases, such as allergic asthma.
Methods: We examined allergic airway inflammation and airway hyperresponsiveness (AHR) in 3 different mouse models, which use either ROG-deficient (ROG(-/-)) mice, ROG transgenic mice, or adoptive transfer of cells.
Results: In ROG(-/-) mice T(H)2 cell differentiation, T(H)2 responses, eosinophilic airway inflammation, and AHR were enhanced. In ROG transgenic mice the levels of eosinophilic airway inflammation and AHR were dramatically reduced. Furthermore, adoptive transfer of T(H)2 cells with increased or decreased levels of ROG expression into the asthmatic mice resulted in reduced or enhanced airway inflammation, respectively.
Conclusion: These results indicate that ROG regulates allergic airway inflammation and AHR in a negative manner, and thus ROG might represent another potential therapeutic target for the treatment of asthmatic patients.

DOI： 10.1016/j.jaci.2008.06.004

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：CURRENT BIOLOGY LTD  

Thelper type2 (Th2) cells produce IL-4, IL-5, and IL-13 and play an important role in humoral immunity and allergic reactions. During Th2 cell differentiation, naive CD4 T cells acquire 'Th2 cell identity', that is, the capability to produce selectively a large amount of Th2 cytokines. Th2 cell identity is maintained in memory Th2 cells. Significant advances in understanding of the molecular requirement for these processes have been made. The expression of GATA3, a master transcription factor for Th2 cell differentiation, is uniquely regulated by several distinct mechanisms. Molecular analyses of memory Th2 cells revealed that cell survival and the maintenance of Th2 cell function are epigenetically regulated by various nuclear factors, including Polycomb and Trithorax molecules.

DOI： 10.1016/j.coi.2008.03.011

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：JAPANESE PHARMACOLOGICAL SOC  

In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced cosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by administration of LPS at the priming phase in wild-type mice, whereas such an increase was not observed in mast cell deficient mice. Adoptive transfer of bone marrow-derived mast cells (BMMC) from wild type but not from Toll-like receptor 4 (TLR4)-deficient mice restored the increased eosinophilic inflammation in mast cell-deficient mice. Moreover, in vitro analysis revealed that treatment of BMMC with LPS resulted in sustained up-regulation of GATA1 expression and increased production of Th2 cytokines (IL-4, IL-5, and IL-13) upon restimulation. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 proteins and subsequent increase in Th2 cytokine production.

DOI： 10.1254/jphs.FM0070202

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DOI： 10.1084/jem.20072000

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DOI： 10.1074/jbc.M804174200

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DOI： 10.1111/j.1365-2567.2008.02854.x

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DOI： 10.1093/intimm/dxn043

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Schnurri (Shn)-2 is a large zinc finger-containing protein, which plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient (Shn-2(-l-)) CD4 T cells, the activation of nuclear factor-KB is up-regulated and their ability to differentiate into T(h)2 is enhanced. Here, we extend our investigation and demonstrate that Shn-2 regulates T(h)2 responses in vivo using an ovalbumin-induced allergic asthma model. Eosinophilic inflammation, mucus hyperproduction and airway hyperresponsiveness (AHR) were all enhanced in Shn-2(-/-) mice. Moreover, eosinophilic infiltration and AHR were enhanced in mice given a transfer of Shn-2(-/-) effector T(h)2. Shn-2 in T(h)2 is thus considered to play an important role as a negative regulator in allergic airway inflammation.

DOI： 10.1093/intimm/dxm042

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Schnurri-2 (Shn-2) is a large zinc-finger containing protein, and it plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient CD4 T cells, the activation of NF-kappa B was up-regulated and their ability to differentiate. into Th2 cells was enhanced. We herein demonstrate that Th1 and Th2 memory cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. Even a week after the transfer of effector Th1/Th2 cells into syngeneic mice, a dramatic decrease in the number of Shn-2-deficient donor T cells was detected particularly in the lymphoid organs. The transferred Shn-2-deficient Th1/Th2 cells express higher levels of the activation marker CD69. No significant defect in the BrdU incorporation in the Shn-2-deficient transferred CD4 T cells was observed. The numbers of apoptotic cells were selectively higher in Shn-2-deficient donor Th1/Th2 cell, population. Moreover, Shn-2-deficient effector Th1 and Th2 cells showed an increased susceptibility to cell death in in vitro cultures with increased expression of FasL. Transfer of Th2 effector cells over-expressing the p65 subunit of NF-kappa B resulted in a decreased number of p65-expressing cells in the lymphoid organs. As expected, T cell-dependent Ab responses after in vivo immunization of Shn-2-deficient mice were significantly reduced. Thus, Shn-2 appears to control the generation of memory Th1/Th2 cells through a change in their susceptibility to cell death.

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Allergic asthma is an airway inflammatory disease characterized by chronically increased expression of multiple inflammatory proteins, including cytokines, chemokines, adhesion molecules, enzymes, and receptors. Several transcription factors are known to play a crucial role in the pathogenesis of chronic inflammatory diseases such as asthma, including signal transducer and activator of transcription factors, nuclear factor-kappaB, nuclear factor of activated T cells, activator protein-1 family proteins, and Th2 cell-related transcription factors including GATA3, JunB, and c-Maf. Modulation of the activity of certain transcription factors has been shown to result in the inhibition of inflammation during asthma. Therefore, both agonists and inhibitors of transcription factors may be potential tools for the treatment of asthma. In this review, we summarize the current knowledge of the role of well-established transcription factors in asthma. © 2007 by Begell House, Inc.

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DOI： 10.1016/j.molimm.2006.11.004

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Background: Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear.
Objective: We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice.
Methods: We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions.
Results: In NC/Nga mice maintained under specific pathogen-free conditions, the capability of T(H)1/T(H)2 and T cytotoxic 1/T cytotoxic 2 (Tc1/Tc2) cell differentiation increased significantly. T-cell antigen receptor-mediated activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase cascade and nuclear factor-kappa B (NF-kappa B) signaling were enhanced in NC/Nga T cells. The expression of T(H)2 cytokines (IL-4, IL-13, and IL-5) and that of GATA-binding protein 3 (GATA3), avian musculoaponeurotic fibrosarcoma (c-Maf), NF-kappa B, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-kappa B mutant-infected T(H)2 cells reduced ear thickness in the mite antigen-induced skin lesion of NC/Nga mice.
Conclusion: Hyperresponsive T(H)2 cells with an enhanced activity of NF-kappa B and AP1 play a crucial role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice.
Clinical implications: These results indicate potential therapeutic usefulness of developing selective inhibitors for NF-kappa B in the treatment of human atopic dermatitis.

DOI： 10.1016/j.jaci.2006.05.024

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Other Link： http://opac.ll.chiba-u.jp/da/curator/900023116/

Language：English   Publisher：NATL ACAD SCIENCES  

In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LIPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-cell-deficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-kappa B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LIPS-treated BMMCs after costimulation with LIPS and IgE/Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.

DOI： 10.1073/pnas.0510685103

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DOI： 10.1016/j.immuni.2006.03.017

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Differentiation of naive CD4 T cells into Th2 cells requires protein expression of GATA3. Interleukin-4 induces STAT6 activation and subsequent GATA3 transcription. Little is known, however, on how T cell receptor-mediated signaling regulates GATA3 and Th2 cell differentiation. Here we demonstrated that T cell receptor-mediated activation of the Ras-ERK MAPK cascade stabilizes GATA3 protein in developing Th2 cells through the inhibition of the ubiquitin-proteasome pathway. Mdm2 was associated with GATA3 and induced ubiquitination on GATA3, suggesting its role as a ubiquitin-protein isopeptide ligase for GATA3 ubiquitination. Thus, the Ras-ERK MAPK cascade controls GATA3 protein stability by a post-transcriptional mechanism and facilitates GATA3-mediated chromatin remodeling at Th2 cytokine gene loci leading to successful Th2 cell differentiation.

DOI： 10.1074/jbc.M502333200

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Both CD4 and CD8 T cells play crucial roles in immune responses in transplantation. Immunosuppressive drugs, such as FK506 and cyclosporin A, block the priming of alloreactive CD4 T-h cells and the subsequent induction of allospecific CD8 cytotoxic effector T cells and inhibit allograft rejection. However, the desire to minimize chronic complications that may arise from the use of immunosuppressive agents drives the search for additional strategies for immunosuppression of allograft rejection. In this study, CD4 or CD8 T cells into which the IL-10 gene is introduced using an adenovirus vector containing human IL-10 (hIL-10) cDNA (Ad-hIL-10) and into mouse T cells transgenic for the Coxsackie virus and adenovirus receptor form a model system to study the effect of administration of IL-10-secreting T cells on the survival of the allogenic skin grafts. Ad-hIL-10-infected CD4 and CD8 T cells secreted a large amount of hIL-10 for 3-4 days in culture in vitro. Ad-hIL-10-infected CD4 T cells administered in vivo could be detected in the spleen for 7 days post-transfer. Significantly prolonged survival of grafts was observed in animals that received either Ad-hIL-10-infected activated CD4 T cells or T(h)2-skewed CD4 T cells as compared with controls. Furthermore, substantial enhancement of the effect was observed in B6.C-H2(bm1)/ByJ transplants. Thus, a direct manipulation of T cells through the introduction of the immunosuppressive cytokine gene IL-10 may be a novel strategy for the control of allograft rejection.

DOI： 10.1093/intimm/dxh256

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DOI： 10.1016/j.ics.2005.08.007

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DOI： 10.1084/jem.20040733

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NK cells differentiate into either NK1 or NK2 cells that produce IFN-gamma or IL-5 and IL-13, respectively. Little is known, however, about the molecular mechanisms that control NK1 and NK2 cell differentiation. To address these questions, we established an in vitro mouse NK1/NK2 cell differentiation culture system. For NK1/NK2 cell differentiation, initial stimulation with PMA and ionomycin was required. The in vitro differentiated NK2 cells produced IL-5 and IL-13, but the levels were 20 times lower than those of Th2 or T cytotoxic (Tc)2 cells. No detectable IL-4 was produced. Freshly prepared NK cells express IL-2Rbeta, IL-2RgammaC, and IL-4Ralpha. After stimulation with PMA and ionomycin, NK cells expressed IL-2Ralpha. NK1 cells displayed higher cytotoxic activity against Yac-1 target cells. The levels of GATA3 protein in developing NK2 cells were approximately one-sixth of those in Th2 cells. Both NK1 and NK2 cells expressed large amounts of repressor of GATA, the levels of which were equivalent to CD8 Tc1 and Tc2 cells and significantly higher than those in Th2 cells. The levels of histone hyperacetylation of the IL-4 and IL-13 gene loci in NK2 cells were very low and equivalent to those in naive CD4 T cells. The production of IL-5 and IL-13 in NK2 cells was found to be STATE dependent. Thus, similar to Th2 cells, NK2 cell development is dependent on STATE, and the low level expression of GATA3 and the high level expression of repressor of GATA may influence the unique type 2 cytokine production profiles of NK2 cells.

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DOI： 10.15036/arerugi.53.1011_2

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Interleukin (IL)-4-induced STAT6 activation and the subsequent up-regulation of GATA3 are crucial for the induction of chromatin remodeling of the Th2 cytokine gene loci as Th2 cells undergo development. This study probes the role of these molecules in the maintenance of memory Th2 cells. IL-4 was not required to maintain the capability for Th2 cytokine production in in vivo generated antigen-specific memory Th2 cells. Histone H3K9/14 hyperacetylation and intergenic transcripts associated with the IL-4 gene locus were preserved in the absence of IL-4, but those associated with the IL-13 gene were partially IL-4-dependent. Histone H3-K4 methylation of the IL-13 and IL-4 gene loci was fully preserved in memory Th2 cells and accompanied by memory cell-specific accumulation of Pol II complex to highly restricted sites. Thus, memory Th2 cells maintain a unique Th2-specific remodeled chromatin in the IL-4 and IL-13 gene loci by active molecular events that are IL-4-independent.

DOI： 10.1074/jbc.M405989200

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GATA3 expression is essential for type-2 helper T (Th2) cell differentiation. GATA3-mediated chromatin remodeling at the Th2 cytokine gene loci, including Th2-specific long range histone hyperacetylation of the interleukin (IL)-13/IL-4 gene loci, occurs in developing Th2 cells. However, little is known about the role of GATA3, if any, in the maintenance of established remodeled chromatin at the Th2 cytokine gene loci. Here, we established a Cre/LoxP-based site-specific recombination system in cultured CD4 T cells using a unique adenovirus-mediated gene transfer technique. This system allowed us to investigate the effect of loss of GATA3 expression in in vitro differentiated Th2 cells. After ablation of GATA3, we detected reduced production of all Th2 cytokines, increased DNA methylation at the IL- 4 gene locus, and decreased histone hyperacetylation at the IL- 5 gene locus but not significantly so at the IL-13/IL-4 gene loci. Thus, GATA3 plays important roles in the maintenance of the Th2 phenotype and continuous chromatin remodeling of the specific Th2 cytokine gene locus through cell division.

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Interleukin 5 ( IL-5) plays a unique role in allergic inflammatory responses, and the understanding of molecular mechanisms underlying the generation of IL-5-producing cells is crucial for the regulation of allergic disorders. Differentiation of naive CD4 T cells into type-2 helper (Th2) cells is accompanied by chromatin remodeling including hyperacetylation of histones H3 and H4 in the nucleosomes associated with the IL-4, IL-13, and IL-5 genes. Histone hyperacetylation of the IL-5 gene displayed a delayed kinetics compared with that of the IL-4 and IL-13 genes, suggesting a distinct remodeling mechanism for the IL-5-gene locus. Here we studied the role of CD28 costimulation in the generation of IL-5-producing cells and the histone hyperacetylation of the IL-5 gene locus. CD28-costimulation selectively enhanced histone hyperacetylation of the IL-5 gene locus that appeared to be mediated through NF-kappaB activation and subsequent up-regulation of GATA3. The CD28 costimulation-sensitive histone hyperacetylation spanned almost the entire intergenic region between the IL-5 and RAD50 accompanied with intergenic transcript. Thus, this is the first demonstration that CD28 costimulation controls a chromatin-remodeling process during Th2 cell differentiation.

DOI： 10.1074/jbc.M401248200

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publisher：OXFORD UNIV PRESS  

CD69, known as an early activation marker antigen on T and B cells, is also expressed on platelets and activated neutrophils, suggesting certain roles in inflammatory diseases. In order to address the role of CD69 in the pathogenesis of arthritis, we established CD69-null mice. CD69-null mice displayed a markedly attenuated arthritic inflammatory response when injected with anti-type II collagen antibodies. Cell transfer experiments with neutrophils, but not T cells or spleen cells, from wild-type mice into CD69-null mice restored the induction of arthritis. These results indicate a critical role for CD69 in neutrophil function in arthritis induction during the effector phase. Thus, CD69 would be a possible therapeutic target for arthritis in human patients.

DOI： 10.1093/intimm/dxg102

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Language：English   Publisher：MOSBY, INC  

Background: Certain immune functions are known to be impaired in human beings exposed to Antarctic winter; in particular, decreased amounts of serum proinflammatory cytokines, such as TNF-alpha and IL-1, were noted. It is not known, however, whether this exposure has any effect on T-cell-mediated acquired immune functions. Objectives: This study aims to investigate whether exposure to Antarctic winter has any effect on T cell-dependent immune functions.
Methods: We assessed changes in various immunologic indicators. including serum levels of various cytokines, peripheral blood Valpha24Vbeta11 natural killer T cell numbers, and T(H)1/T(H)2 ratios of 40 Japanese personnel exposed to an Antarctic winter. Also, a 2-month inland traverse was executed during the isolation, and the effect on the above indicators was assessed.
Results: All subjects were healthy during the Antarctic isolation. The levels of serum TNF-alpha, IL-1Ra, IL-6, and IL-1beta were dramatically reduced and remained at low levels throughout the isolation. The decrease in the levels of TNF-alpha and IL-1Ra was more pronounced during the inland traverse than during the rest of the isolation. The percentage of Valpha24Vbeta11 natural killer T cells was significantly increased at the midpoint of the isolation. Most interestingly, T(H)1/T(H)2 ratio was increased significantly, and this T(H)1 bias was most prominent at the late point of the isolation.
Conclusions: Exposure to an Antarctic winter appeared to induce T(H)1-skewed immunity in human beings. (J Allergy Clin Immunol 2003;111:1353-60.).

DOI： 10.1067/mai.2003.1504

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Language：English   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Th2 cells are generated from naive CD4 T cells upon T cell receptor (TCR) recognition of antigen and IL-4 stimulation and play crucial roles in humoral immunity against infectious microorganisms and the pathogenesis of allergic and autoimmune diseases. A tyrosine phosphatase, SHP-1, that contains src homology 2 (SH2) domains is recognized as a negative regulator for various intracellular signaling molecules, including those downstream of the TCR and the IL-4 receptor. Here we assessed the role of SHP-1 in Th1/Th2 cell differentiation and in the development of Th2-dependent allergic airway inflammation by using a natural SHP-1 mutant, the motbeaten mouse. CD4 T cells appear to develop normally in the heterozygous motheaten (me/+) thymus even though they express decreased amounts of SHP-1 (about one-third the level of wild-type thymus). The me/+ naive splenic CD4 T cells showed enhanced activation by IL-4 receptor-mediated signaling but only marginal enhancement of TCR-mediated signaling. Interestingly, the generation of Th2 cells was increased and specific cytokine production of mast cells was enhanced in me/+ mice. In an OVA-induced allergic airway inflammation model, eosinophilic inflammation, mucus hyperproduction, and airway hyperresponsiveness were enhanced in me/+ mice. Thus, SHP-1 may have a role as a negative regulator in the development of allergic responses, such as allergic asthma.

DOI： 10.1172/JCI200315719

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DOI： 10.1016/S1074-7613(03)00210-3

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Language：English   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Differentiation of naive CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling of Th2 cytokine gene loci. Hyperacetylation of histone H3 on nucleosomes associated with the interleukin (IL)-4, IL-13 and IL-5 genes was observed in developing Th2 cells but not in Th1 cells. Histone hyperacetylation on IL-5 gene-associated nucleosomes was Th2-specific but occurred with delayed kinetics, and hyperacetylation on RAD50 gene-associated nucleosomes was T cell antigen receptor stimulation-dependent but not Th2-specific. The induction of the Th2-specific histone hyperacetylation was STAT6- and GATA3-dependent, and interestingly, it was accompanied by the expression of intergenic transcripts within the IL-13 and IL-4 gene loci. A conserved GATA3 response element (CGRE) containing four GATA consensus sequences was identified 1.6 kbp upstream from the IL-13 gene, corresponding with the 5'-border of the Th2-specific histone hyperacetylation region. The CGRE was shown to bind to GATA3, histone acetyltransferase complexes including CBP/p300, and RNA polymerase IL Also, the CGRE showed a significant enhancing effect on the Th2 cytokine gene promoters. Thus, the CGRE may play a crucial role for GATA3-mediated targeting and downstream spreading of core histone hyperacetylation within the IL-13 and IL-4 gene loci.

DOI： 10.1074/jbc.M205876200

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Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

Oral tolerance is an important physiological component of the immune system whereby the organism avoids dangerous reactions such as hypersensitivity to ingested food proteins and other luminal Ags which may cause tissue damage and inflammation. In addition, it has been shown in animal models and in humans that oral tolerance can be applied to controlling undesired immune responses, including autoimmune diseases, allergies, and organ transplant rejections. However, the molecular mechanisms of oral tolerance have been poorly defined. In this study, we investigated the molecular basis underlying the hyporesponsiveness of orally tolerant CD4 T cells using a TCR transgenic mouse system in which oral tolerance was induced by long-term feeding with high dose Ag. We demonstrate that the hyporesponsive state of the CD4 T cells was maintained by a selective impairment in the TCR-induced calcium/NFAT signaling pathway and in the IL-2R-induced degradation of p27(kip1) and cell cycle progression. Thus, physiological mucosal tolerance is revealed to be associated with a unique type of T cell hyporesponsiveness which differs from previously described anergic T cells.

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In this study we investigate the stage at which developing T cells in the thymus acquire the ability to differentiate into T(h)1 and T(h)2 cells. We addressed this question by using sorted heat-stable antigen (HSA)(+) and HSA(-) CD4 single-positive (SP) thymocytes prepared from ovalbumin-specific TCRalphabeta transgenic mice and an in vitro T(h)1/T(h)2 differentiation culture system. HSA(-) CD4 SP thymocytes show nearly full functional capacity to differentiate into either T(h)1 or T(h)2 cells. A dramatic difference was observed, however, between HSA(+) and HSA(-) CD4 SP thymocytes in the efficiency for T(h)1 cell differentiation. TCR function of HSA(+) CD4 SP thymocytes appeared to be fully developed because antigen-induced proliferation and IL-2 production were essentially equivalent to that of HSA(-) CD4 SP thymocytes. However, the levels in IL-12 receptor (IL-12R) beta2 chain expression following anti-TCR stimulation were dramatically low in the HSA(+) CD4 SP thymocytes. Decreased IL-12-induced STAT4 phosphorylation was also observed. Moreover, IL-12-dependent transcriptional up-regulation of T-bet and STAT4 was deficient in the HSA(+) CD4 SP thymocytes. Thus, the poor capacity of HSA(+) CD4 SP thymocytes to proceed to T(h)1 cell differentiation appears to be at least partly due to underdeveloped capacity in IL-12R expression and function.

DOI： 10.1093/intimm/dxf057

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Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

The central role for Th2 cells in the development of Ag-induced airway hyperresponsiveness and eosinophilic inflammation is well documented. We have reported a crucial role for TCR-induced activation of the Ras/extracellular signal-regulated kinase mitogen-activated protein kinase cascade in Th2 cell differentiation. Here, we show that the development of both OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation in a mouse asthma model are attenuated in transgenic mice by the overexpression of enzymatically inactive Ras molecules in T cells. In addition, reduced levels of IL-5 production and eosinophilic inflammation induced by nematode infection (Nippostrongylus brasiliensis or Heligmosomoides polygyrus) were detected. Thus, the level of Ras activation in T cells appears to determine Th2-dependent eosinophilic inflammation and Ag-induced airway hyperresponsiveness.

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Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

During development in the thymus, mature CD4(+) or CD8(+) cells are derived from immature CD4(+)CD8(+) cells through a series of selection events. One of the hallmarks of this maturation process is the expression of CD69, which first appears on thymocytes as they begin positive selection. We have used blockade and overexpression of CD69 to determine the role of CD69 in thymocyte development. Blockade of CD69 led to a reduction in single-positive cells and a concomitant increase in double-positive cells in the thymus. Overexpression of a CD69 transgene in the thymus resulted in a dramatic increase in both CD8SP and CD4SP cells. Coexpression with a TCR transgene demonstrated that both positive and negative selection were enhanced by the increased levels of CD69 on thymocytes. Finally, mice overexpressing CD69 displayed a sharp reduction in the number of T cells in the spleen and lymph node. Taken as a whole, these data suggest the involvement of CD69 in the process of selection and maturation during the trafficking of thymocytes to the medulla.

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DOI： 10.15036/arerugi.50.971_4

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DOI： 10.15036/arerugi.50.851_1

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Language：Japanese   Publisher：千葉大学  

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.48.926_2

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

DOI： 10.15036/arerugi.48.895_2

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Applicant：国立大学法人 千葉大学, 旭市, 公益財団法人かずさDNA研究所, 株式会社DNAチップ研究所

Application no：特願2011-156921  Date applied：2011.7

Announcement no：特開2013-021932  Date announced：2013.2

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Applicant：国立大学法人 千葉大学, 公益財団法人かずさDNA研究所

Application no：特願2011-076653  Date applied：2011.3

Announcement no：特開2012-210167  Date announced：2012.11

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Applicant：国立大学法人 千葉大学, 公益財団法人かずさDNA研究所

Application no：特願2011-076653  Date applied：2011.3

Announcement no：特開2012-210167  Date announced：2012.11

Patent/Registration no：特許第5858418号  Date issued：2015.12

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Applicant：国立大学法人 千葉大学, 財団法人かずさディー・エヌ・エー研究所

Application no：特願2006-093086  Date applied：2006.3

Announcement no：特開2007-259835  Date announced：2007.10

Patent/Registration no：特許第4863452号  Date issued：2011.11

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Applicant：国立大学法人 千葉大学, 財団法人かずさディー・エヌ・エー研究所

Application no：特願2006-093086  Date applied：2006.3

Announcement no：特開2007-259835  Date announced：2007.10

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