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Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.

ABSTRACT: NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of CD4(+)CD25(-) effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs inhibited the expression of retinoic acid-related orphan receptor ?t but not T-bet, whereas nTregs suppressed T-bet but not retinoic acid-related orphan receptor ?t expression. The NO-Treg-mediated suppression of Th17 was partially cell contact-dependent and was associated with IL-10. In vivo, adoptively transferred NO-Tregs potently attenuated experimental autoimmune encephalomyelitis. The disease suppression was accompanied by a reduction of Th17, but not Th1 cells in the draining lymph nodes, and a decrease in the production of IL-17, but an increase in IL-10 synthesis. Our results therefore demonstrate the differential suppressive function between NO-Tregs and nTregs and indicate specialization of the regulatory mechanism of the immune system.

SUBMITTER: Niedbala W

PROVIDER: S-EPMC3785138 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.

Niedbala Wanda W Besnard Anne-Gaelle AG Jiang Hui R HR Alves-Filho Jose C JC Fukada Sandra Y SY Nascimento Daniela D Mitani Akio A Pushparaj Peter P Alqahtani Mohammed H MH Liew Foo Y FY

Journal of immunology (Baltimore, Md. : 1950) 20130529 1

NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4(+)CD25(+)Foxp3(-) regulatory T cells (NO-Tregs) that suppress the functions of CD4(+)CD25(-) effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs ...[more]

PMID: 23720815

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Project description:BACKGROUND:How the gut microbiota regulates intestinal homeostasis is not completely clear. Gut microbiota metabolite short-chain fatty acids (SCFAs) have been reported to regulate T-cell differentiation. However, the mechanisms underlying SCFA regulation of T-cell differentiation and function remain to be investigated. METHODS:CBir1, an immunodominant microbiota antigen, transgenic T cells were treated with butyrate under various T-cell polarization conditions to investigate butyrate regulation of T-cell differentiation and the mechanism involved. Transfer of butyrate-treated CBir T cells into Rag1-/- mice was performed to study the in vivo role of such T cells in inducing colitis. RESULTS:Although butyrate promoted Th1 cell development by promoting IFN-? and T-bet expression, it inhibited Th17 cell development by suppressing IL-17, Ror?, and Ror?t expression. Interestingly, butyrate upregulated IL-10 production in T cells both under Th1 and Th17 cell conditions. Furthermore, butyrate induced T-cell B-lymphocyte-induced maturation protein 1 (Blimp1) expression, and deficiency of Blimp1 in T cells impaired the butyrate upregulation of IL-10 production, indicating that butyrate promotes T-cell IL-10 production at least partially through Blimp1. Rag1-/- mice transferred with butyrate-treated T cells demonstrated less severe colitis, compared with transfer of untreated T cells, and administration of anti-IL-10R antibody exacerbated colitis development in Rag-/- mice that had received butyrate-treated T cells. Mechanistically, the effects of butyrate on the development of Th1 cells was through inhibition of histone deacetylase but was independent of GPR43. CONCLUSIONS:These data indicate that butyrate controls the capacity of T cells in the induction of colitis by differentially regulating Th1 and Th17 cell differentiation and promoting IL-10 production, providing insights into butyrate as a potential therapeutic for the treatment of inflammatory bowel disease.

Project description:BackgroundAglaia (Meliaceae) species are used for treating autoimmune disorders and allergic diseases in Asian countries. Rocaglamide, an extract obtained from Aglaia species, exhibits suppressive effect by regulating the T cell subset balance and cytokine network in cancer. However, whether it can be used in organ transplantation is unknown. In this study, we investigated the antirejection effect and mechanism of action of rocaglamide in a mouse cardiac allograft model.MethodsSurvival studies were performed by administering mice with phosphate-buffered saline (PBS) (n = 6) and rocaglamide (n = 8). Heart grafts were monitored until they stopped beating. After grafting, the mice were sacrificed on day 7 for histological, mixed lymphocyte reaction (MLR), enzyme-linked immunosorbent assay (ELISA), and flow cytometric analyses.ResultsRocaglamide administration significantly prolonged the median survival of the grafts from 7 to 25 days compared with PBS treatment (P < 0.001). On posttransplantation day 7, the rocaglamide-treated group showed a significant decrease in the percentage of Th1 cells (7.9 ± 0.9% vs. 1.58 ± 0.5%, P < 0.001) in the lymph nodes and spleen (8.0 ± 2.5% vs. 2.4 ± 1.3%, P < 0.05). Rocaglamide treatment also significantly inhibited the production of Th17 cells (6.4 ± 1.0% vs. 1.8 ± 0.4%, P < 0.01) in the lymph nodes and spleen (5.9 ± 0.3% vs. 2.9 ± 0.8%, P < 0.01). Furthermore, the prolonged survival of the grafts was associated with a significant decrease in IFN-γ and IL-17 levels. Our results also showed that NF-AT activation was inhibited by rocaglamide, which also induced p38 and Jun N-terminal kinase (JNK) phosphorylation in Jurkat T cells. Furthermore, by using inhibitors that suppressed p38 and JNK phosphorylation, rocaglamide-mediated reduction in NF-AT protein levels was prevented.ConclusionWe identified a new immunoregulatory property of rocaglamide, wherein it was found to regulate oxidative stress response and reduce inflammatory cell infiltration and organ injury, which have been associated with the inhibition of NF-AT activation in T cells.

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Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.

Publications

Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function.

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