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Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.

ABSTRACT: Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-? production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-? mRNA. Sustained expression of IFN-? protein by effector T cells was dependent on common ?-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis.

SUBMITTER: Mahne AE

PROVIDER: S-EPMC4369402 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.

Mahne Ashley E AE Klementowicz Joanna E JE Chou Annie A Nguyen Vinh V Tang Qizhi Q

Journal of immunology (Baltimore, Md. : 1950) 20150302 7

Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accum ...[more]

PMID: 25732730

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Project description:Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+ CD127+ CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4+ CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+ CD127+ CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+ CD127+ CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+ CD127+ CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. CONCLUSION:Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584).

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Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.

Publications

Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.

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