| 1. |
Kei Nishioka, Haruei Ogino, Takatoshi Chinen, Eikichi Ihara, Yoshimasa Tanaka, Kazuhiko Nakamura, Yoshihiro Ogawa, Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease., Journal of gastroenterology, 10.1007/s00535-021-01819-7, 56, 11, 976-987, 2021.08, BACKGROUND: Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. METHODS: We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. RESULTS: There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. CONCLUSIONS: The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.. |
| 2. |
Hideo Yasukawa, Masanobu Ohishi, Hiroyuki Mori, Masaaki Murakami, Takatoshi Chinen, Daisuke Aki, Toshikatsu Hanada, Kiyoshi Takeda, Shizuo Akira, Masahiko Hoshijima, Toshio Hirano, Kenneth R Chien, Akihiko Yoshimura, IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages., Nature immunology, 4, 6, 551-6, 2003.06, Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.. |
| 3. |
Kyoko Inagaki-Ohara, Takatoshi Chinen, Goro Matsuzaki, Atsuo Sasaki, Yukiko Sakamoto, Kenji Hiromatsu, Fukumi Nakamura-Uchiyama, Yukifumi Nawa, Akihiko Yoshimura, Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation., Journal of immunology (Baltimore, Md. : 1950), 173, 2, 1390-8, 2004.07, Intestinal intraepithelial lymphocytes (IEL) bearing TCRgammadelta represent a major T cell population in the murine intestine. However, the role of gammadelta IEL in inflammatory bowel diseases (IBD) remains controversial. In this study, we show that gammadelta IEL is an important protective T cell population against IBD. gammadelta T cell-deficient (Cdelta(-/-)) mice developed spontaneous colitis with age and showed high susceptibility to Th1-type 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis at a young age. Transfer of gammadelta IEL to Cdelta(-/-) mice ameliorated TNBS-induced colitis, which correlated with decrease of IFN-gamma and TNF-alpha production and an increase of TGF-beta production by IEL. Furthermore, a high level of IL-15, which inhibits activation-induced cell death to terminate inflammation, was expressed more in intestinal epithelial cells (EC) from TNBS-treated Cdelta(-/-) mice than in those from wild-type mice. EC from wild-type mice significantly suppressed the IFN-gamma production of IEL from TNBS-treated Cdelta(-/-) mice, whereas EC from TNBS-treated Cdelta(-/-) mice did not. These data indicate that gammadelta IEL play important roles in controlling IBD by regulating mucosal T cell activation cooperated with EC function. Our study suggests that enhancement of regulatory gammadelta T cell activity is a possible new cell therapy for colitis.. |
| 4. |
Takatoshi Chinen, Tadashi Misawa, Koki Yoshida, Toshifumi Nasu, Shigeru Kubo, Satoshi Toyoshima, Takashi Yao, Naohiko Harada, Esophageal submucosal gland duct adenoma., Gastrointestinal endoscopy, 60, 5, 798-9, 2004.11. |
| 5. |
Takatoshi Chinen, Tadashi Misawa, Takashi Yao, Toshifumi Nasu, Koki Yoshida, Shigeru Kubo, Satoshi Toyoshima, Tsugio Sakaguchi, Naohiko Harada, Pedunculated cap polyps preceding the development of cap polyposis: case report., Gastrointestinal endoscopy, 61, 2, 338-40, 2005.02. |
| 6. |
Takatoshi Chinen, Takashi Kobayashi, Hisanobu Ogata, Giichi Takaesu, Hiromi Takaki, Masayuki Hashimoto, Hideo Yagita, Hajime Nawata, Akihiko Yoshimura, Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNgamma and IL-4 are involved., Gastroenterology, 130, 2, 373-88, 2006.02, BACKGROUND & AIMS: The suppressor of cytokine signaling-1 (SOCS1) is a potent negative regulator of various cytokines and it has been implicated in the regulation of immune responses. However, the role of SOCS1 in inflammatory bowel diseases (IBDs) has not been clarified. To determine the role of SOCS1 in colitis, we generated SOCS1/T-cell receptor alpha (TCRalpha) double knockout (DKO) mice. METHODS: The depletion of interferon gamma (IFNgamma) and IL-4 was achieved by crossing the DKO mice with IFNgamma knockout (KO) mice and by the administration of anti-IL-4 antibody, respectively. The activation of cytokine-induced transcription factors was determined by Western blotting with phosphorylation-specific antibodies, and the induction of inflammatory factors was measured by reverse-transcription polymerase chain reaction. RESULTS: Much more severe colitis developed in 100% of the DKO mice within 9 weeks of age than in TCRalpha-KO mice. Although the proportion and the activation status of CD4(+) TCRalpha(-)beta(+) T cells in DKO mice were similar to those in TCRalpha-KO mice, signal transducer and activator of transcription 1, nuclear factor kappaB, and their target genes were hyperactivated in infiltrated mononuclear cells and colonic epithelial cells in DKO mice. Cytokine-depletion experiments showed that exacerbated colitis in the DKO mice was dependent on both IFNgamma and IL-4. SOCS1-deficient cells were hypersensitive to IFNgamma, IL-4, and lipopolysaccharides, depending on the target genes. CONCLUSIONS: SOCS1 plays an important role in preventing murine colitis by restricting the cytokine signals. SOCS1/TCRalpha DKO mice could be a useful model for investigating human IBD.. |
| 7. |
Toshikatsu Hanada, Takashi Kobayashi, Takatoshi Chinen, Kazuko Saeki, Hiromi Takaki, Keiko Koga, Yasumasa Minoda, Takahito Sanada, Tomoko Yoshioka, Hiromitsu Mimata, Seiya Kato, Akihiko Yoshimura, IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice., The Journal of experimental medicine, 203, 6, 1391-7, 2006.06, Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.. |
| 8. |
Hisanobu Ogata, Takashi Kobayashi, Takatoshi Chinen, Hiromi Takaki, Takahito Sanada, Yasumasa Minoda, Keiko Koga, Giichi Takaesu, Yoshihiko Maehara, Mitsuo Iida, Akihiko Yoshimura, Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis., Gastroenterology, 131, 1, 179-93, 2006.07, BACKGROUND & AIMS: A recent study has suggested that the methylation silencing of the suppressor of cytokine signaling-3 (SOCS3), a negative regulator of interleukin-6-related cytokines, could be involved in hepatocellular carcinoma (HCC). However, the roles of SOCS3 in hepatocellular carcinogenesis and hepatitis have not been established. We investigated the effect of deleting the SOCS3 gene on the development of hepatitis and HCC in hepatitis C virus-infected patients and mouse models. METHODS: The expression of SOCS genes in HCC and non-HCC regions of patient samples was determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The conditional knockout approach in mice was used to determine the hepatocyte-specific roles of SOCS3. To generate a liver-specific deletion, floxed SOCS3 (SOCS3(fl/fl)) mice were crossed with albumin-Cre transgenic mice. Hepatitis and HCC were induced by administering concanavalin A and diethylnitrosamine, respectively. RESULTS: SOCS3 expression was reduced in the HCC regions compared with the non-HCC regions. Carcinogen-induced hepatic tumor development was enhanced by deletion of the SOCS3 gene, which was associated with higher levels of the targets of signal transducers and activators of transcription (ie, B-cell lymphoma-XL, B-cell lymphoma-2, C-myelocytomatosis, cyclin D1, and vascular endothelial growth factor). In the concanavalin A-mediated hepatitis model, deletion of the SOCS3 gene in the hepatocytes protected against liver injury through suppression of interferon-gamma signaling and induction of the antiapoptotic protein Bcl-XL. CONCLUSIONS: Deletion of the SOCS3 gene in hepatocytes promotes the activation of STAT3, resistance to apoptosis, and an acceleration of proliferation, resulting in enhanced hepatitis-induced hepatocarcinogenesis.. |
| 9. |
Yumiko Matsumura, Takashi Kobayashi, Kenji Ichiyama, Ryoko Yoshida, Masayuki Hashimoto, Tomohito Takimoto, Kentaro Tanaka, Takatoshi Chinen, Takashi Shichita, Tony Wyss-Coray, Katsuaki Sato, Akihiko Yoshimura, Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells., Journal of immunology (Baltimore, Md. : 1950), 179, 4, 2170-9, 2007.08, Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3(+) Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3(+) T cell-inducing tolerogenic DCs. SOCS3(-/-) DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3(-) effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3(+) Treg cells were selectively expanded by SOCS3(-/-) DCs. Adoptive transfer of SOCS3(-/-) DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3(+) T cell expansion was blocked by anti-TGF-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta plays an essential role in the expansion of Foxp3(+) Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.. |
| 10. |
Takehiro Torisu, Mako Nakaya, Satoko Watanabe, Masayuki Hashimoto, Hideyuki Yoshida, Takatoshi Chinen, Ryoko Yoshida, Fuyuki Okamoto, Toshikatsu Hanada, Kumiko Torisu, Giichi Takaesu, Takashi Kobayashi, Hideo Yasukawa, Akihiko Yoshimura, Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis., Hepatology (Baltimore, Md.), 10.1002/hep.22214, 47, 5, 1644-54, 2008.05, UNLABELLED: Acute liver failure is associated with significant mortality. However, the underlying pathophysiological mechanism is not yet fully understood. Suppressor of cytokine signaling-1 (SOCS1), which is a negative-feedback molecule for cytokine signaling, has been shown to be rapidly induced during liver injury. Here, using liver-specific SOCS1-conditional-knockout mice, we demonstrated that SOCS1 deletion in hepatocytes enhanced concanavalin A (ConA)-induced hepatitis, which has been shown to be dependent on activated T and natural killer T (NKT) cells. Although serum cytokine level and NKT cell activation were similar in wild-type (WT) and SOCS1-deficient mice after ConA treatment, proapoptotic signals, including signal transducers and activators of transcription 1 (STAT1) and Jun-terminal kinase (JNK) activation, were enhanced in SOCS1-deficient livers compared with those in WT livers. SOCS1-deficient hepatocytes had higher expression of Fas antigen and were more sensitive to anti-Fas antibody-induced apoptosis than were WT hepatocytes. Furthermore, SOCS1-deficient hepatocytes were more sensitive to tumor necrosis factor (TNF)-alpha-induced JNK activation and apoptosis. These data indicate that SOCS1 is important to the prevention of hepatocyte apoptosis induced by Fas and TNF-alpha. In contrast, SOCS1 overexpression in the liver by adenoviral gene transfer prevented ConA-induced liver injury. CONCLUSION: These findings indicate that SOCS1 plays important negative roles in fulminant hepatitis and that forced expression of SOCS1 is therapeutic in preventing hepatitis.. |
| 11. |
Hiromi Takaki, Kenji Ichiyama, Keiko Koga, Takatoshi Chinen, Giichi Takaesu, Yuki Sugiyama, Shigeaki Kato, Akihiko Yoshimura, Takashi Kobayashi, STAT6 Inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor., The Journal of biological chemistry, 10.1074/jbc.M801123200, 283, 22, 14955-62, 2008.05, It has been shown that transforming growth factor beta1 (TGF-beta1) is critical in the generation of CD4(+)CD25(+)Foxp3(+)-inducible regulatory T cells (iTregs) from naïve CD4(+)T cells. However, in contrast to natural Tregs, TGF-beta1-induced iTregs rapidly lose both Foxp3 expression and suppression activity. We found that TGF-beta1-induced Foxp3 levels were maintained by the addition of the anti-interleukin 4 (IL-4) antibody or by STAT6 gene deletion. Thus, IL-4 is an important suppressor of Foxp3 induction, and T helper 2 development is a major cause for the disappearance of iTreg during long culture. Using promoter analysis in EL4 cells and primary T cells, we identified a silencer region containing a STAT6 binding site. STAT6 binding to this site reduced TGF-beta1-mediated Foxp3 promoter activation and chromatin modification. Retinoic acid has also been shown to suppress loss of Foxp3 induced by TGF-beta1. Retinoic acid in the presence of TGF-beta1 reduced STAT6 binding to the Foxp3 promoter and enhanced histone acetylation, thereby reverting the effect of IL-4. We propose that antagonistic agents for neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and the promotion of tolerance in Th2-dominated diseases such as allergy.. |
| 12. |
Kenji Ichiyama, Hideyuki Yoshida, Yu Wakabayashi, Takatoshi Chinen, Kazuko Saeki, Mako Nakaya, Giichi Takaesu, Shohei Hori, Akihiko Yoshimura, Takashi Kobayashi, Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat., The Journal of biological chemistry, 10.1074/jbc.M801286200, 283, 25, 17003-8, 2008.06, The cytokine, transforming growth factor-beta1 (TGF-beta1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-beta1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gammat (RORgammat), was rapidly induced by TGF-beta1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that RORgammat binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORgammat-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORgammat through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORgammat-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.. |
| 13. |
Takatoshi Chinen, Pavel Y Volchkov, Alexander V Chervonsky, Alexander Y Rudensky, A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota., The Journal of experimental medicine, 10.1084/jem.20101235, 207, 11, 2323-30, 2010.10, Suppression mediated by regulatory T cells (T reg cells) represents a unique, cell-extrinsic mechanism of in-trans negative regulation that restrains multiple types of immune cells. The loss of T reg cells leads to fatal, highly aggressive, and widespread immune-mediated lesions. This severe autoimmunity may be driven by commensal microbiota, the largest source of non-self ligands activating the innate and adaptive immune systems. Alternatively, T reg cells may primarily restrain T cells with a diverse self-major histocompatibility complex (MHC)-restricted T cell receptor repertoire independently of commensal microbiota. In this study, we demonstrate that in germ-free (GF) mice, ablation of the otherwise fully functional T reg cells resulted in a systemic autoimmune lympho- and myeloproliferative syndrome and tissue inflammation comparable with those in T reg cell-ablated conventional mice. Importantly, there were two exceptions: in GF mice deprived of T reg cells, the inflammation in the small intestine was delayed, whereas exocrine pancreatitis was markedly accelerated compared with T reg cell-ablated conventional mice. These findings suggest that the main function of T reg cells is restraint of self-MHC-restricted T cell responsiveness, which, regardless of the presence of commensal microbiota, poses a threat of autoimmunity.. |
| 14. |
Reiko Takahashi, Shuhei Nishimoto, Go Muto, Takashi Sekiya, Taiga Tamiya, Akihiro Kimura, Rimpei Morita, Mayako Asakawa, Takatoshi Chinen, Akihiko Yoshimura, SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production., The Journal of experimental medicine, 10.1084/jem.20110428, 208, 10, 2055-67, 2011.09, Regulatory T cells (T(reg) cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of T(reg) cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1(-/-) T(reg) cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2(-/-) mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1(-/-) T(reg) cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ(-/-)Socs1(-/-) T(reg) cells, the restriction of IFN-γ-STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ(-/-)Socs1(-/-) T(reg) cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ(-/-)Socs1(+/+) T(reg) cells and could not suppress colitis induced by naive T cells in Rag2(-/-) mice. In vitro experiments suggested that cytokines produced by Socs1(-/-) T(reg) cells and Ifnγ(-/-)Socs1(-/-) T(reg) cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in T(reg) cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.. |
| 15. |
Takatoshi Chinen, Kyoko Komai, Go Muto, Rimpei Morita, Naoko Inoue, Hideyuki Yoshida, Takashi Sekiya, Ryoko Yoshida, Kazuhiko Nakamura, Ryoichi Takayanagi, Akihiko Yoshimura, Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance., Nature communications, 10.1038/ncomms1181, 2, 190-190, 2011.02, Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10(-/-)Rag2(-/-) mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1(-/-)Rag2(-/-) mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs.. |
| 16. |
Takatoshi Chinen, Alexander Y Rudensky, The effects of commensal microbiota on immune cell subsets and inflammatory responses., Immunological reviews, 10.1111/j.1600-065X.2011.01083.x, 245, 1, 45-55, 2012.01, Billions of years of coevolution shaped the mutually beneficial relationships between metazoans and symbiotic commensal microorganisms. Commensal microorganisms profoundly affect the physiology of the host and provide the host with survival advantages in several ways, while they could also trigger pathogenic immune responses and threaten the well-being of the host. Recent advances in DNA sequencing technology enabled the analysis of commensal microbiota, and improvements in the techniques of culturing gut-resident microorganisms and of rearing gnotobiotic rodents have made it possible to assess the effect of individual component of microbial communities on host physiology. In this review, we discuss the current understanding of the interactions of commensal microbiota with the host immune system.. |
| 17. |
Steven Z Josefowicz, Rachel E Niec, Hye Young Kim, Piper Treuting, Takatoshi Chinen, Ye Zheng, Dale T Umetsu, Alexander Y Rudensky, Extrathymically generated regulatory T cells control mucosal TH2 inflammation., Nature, 10.1038/nature10772, 482, 7385, 395-9, 2012.02, A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation. Regulatory T (T(reg)) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tT(reg) cells) and in the periphery (induced (i)T(reg) cells), and their dual origin implies a division of labour between tT(reg) and iT(reg) cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iT(reg) cells in mice did not lead to unprovoked multi-organ autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (T(H)1) and T(H)17 cells. However, mice deficient in iT(reg) cells spontaneously developed pronounced T(H)2-type pathologies at mucosal sites--in the gastrointestinal tract and lungs--with hallmarks of allergic inflammation and asthma. Furthermore, iT(reg)-cell deficiency altered gut microbial communities. These results suggest that whereas T(reg) cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of T(reg) cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.. |
| 18. |
Yongqiang Feng, Aaron Arvey, Takatoshi Chinen, Joris van der Veeken, Georg Gasteiger, Alexander Y Rudensky, Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus., Cell, 10.1016/j.cell.2014.07.031, 158, 4, 749-763, 2014.08, In multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states.. |
| 19. |
Takatoshi Chinen, Arun K Kannan, Andrew G Levine, Xiying Fan, Ulf Klein, Ye Zheng, Georg Gasteiger, Yongqiang Feng, Jason D Fontenot, Alexander Y Rudensky, An essential role for the IL-2 receptor in Treg cell function., Nature immunology, 10.1038/ni.3540, 17, 11, 1322-1333, 2016.11, Regulatory T cells (Treg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of Treg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4+ T cells but was important for limiting the activation of CD8+ T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of Treg cells separable from signaling via the T cell antigen receptor.. |
| 20. |
Clarissa Campbell, Stanislav Dikiy, Shakti K Bhattarai, Takatoshi Chinen, Fanny Matheis, Marco Calafiore, Beatrice Hoyos, Alan Hanash, Daniel Mucida, Vanni Bucci, Alexander Y Rudensky, Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance., Immunity, 10.1016/j.immuni.2018.04.013, 48, 6, 1245-1257, 2018.06, The mammalian gut microbiota provides essential metabolites to the host and promotes the differentiation and accumulation of extrathymically generated regulatory T (pTreg) cells. To explore the impact of these cells on intestinal microbial communities, we assessed the composition of the microbiota in pTreg cell-deficient and -sufficient mice. pTreg cell deficiency led to heightened type 2 immune responses triggered by microbial exposure, which disrupted the niche of border-dwelling bacteria early during colonization. Moreover, impaired pTreg cell generation led to pervasive changes in metabolite profiles, altered features of the intestinal epithelium, and reduced body weight in the presence of commensal microbes. Absence of a single species of bacteria depleted in pTreg cell-deficient animals, Mucispirillum schaedleri, partially accounted for the sequelae of pTreg cell deficiency. These observations suggest that pTreg cells modulate the metabolic function of the intestinal microbiota by restraining immune defense mechanisms that may disrupt a particular bacterial niche.. |
| 21. |
Keita Fukaura, Yoichiro Iboshi, Haruei Ogino, Eikichi Ihara, Kazuhiko Nakamura, Yuichiro Nishihara, Kei Nishioka, Takatoshi Chinen, Tsutomu Iwasa, Akira Aso, Ayako Goto, Kazuhiro Haraguchi, Hirotada Akiho, Naohiko Harada, Yoshihiro Ogawa, Mucosal Profiles of Immune Molecules Related to T Helper and Regulatory T Cells Predict Future Relapse in Patients With Quiescent Ulcerative Colitis., Inflammatory bowel diseases, 10.1093/ibd/izy395, 25, 6, 1019-1027, 2019.05, BACKGROUND: T helper (Th)- and regulatory T (Treg) cell-related immune molecules are implicated in ulcerative colitis (UC). However, the association between their mucosal expression during remission and the subsequent clinical course of UC is unknown. METHODS: The expression of cytokines and transcription factors related to Th1, Th2, Th17, and Treg in endoscopic mucosal biopsy specimens from 40 UC patients in clinical remission and 9 controls was measured by quantitative polymerase chain reaction. The relationship between their expression patterns, as stratified by Mayo Endoscopic Subscore (MES), and any future relapse was evaluated by univariate and multivariate analyses. RESULTS: Six of 40 patients (baseline MES 0/1/2, 22/14/4) experienced a relapse during the study period (median, 37 months). At baseline, even in the MES0 patients, the interleukin (IL)-17A of the patients was significantly upregulated in comparison with controls (P = 0.0351). Future relapse was associated with a higher baseline expression of IL-17A, IL-17F, and IL-21 in MES0/1, and the upregulation of IL-17F and IL-21 remained statistically significant when limited to MES0 patients. Kaplan-Meier analysis revealed that as a single marker, a higher IL-21 level best grouped patients with an increased risk of relapse (P = 0.0042). Furthermore, a multivariate model that consisted of IL-21 and T-bet showed an even greater value (P = 0.0001). CONCLUSIONS: The profiles of Th/Treg-related gene expression in the colonic mucosa are altered, even during clinical and endoscopic remission of UC, with a detectable Th17-predominant profile predicting future relapse. This association might represent latent immune dysregulation during disease quiescence and has the potential to be utilized to improve patient care.. |
