SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Takahashi, Reiko; Nishimoto, Shuhei; Muto, Go; Sekiya, Takashi; Tamiya, Taiga; Kimura, Akihiro; Morita, Rimpei; Asakawa, Mayako; Chinen, Takatoshi; Yoshimura, Akihiko

doi:10.1084/jem.20110428

Cited by 172 publications

(203 citation statements)

References 47 publications

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“…It seemed unlikely to be THEMIS (44), because it strongly underexpressed in Treg cells. SOCS1 also seemed an unlikely candidate, even though it is required for Foxp3 expression and Treg specification (45), because SOCS1 overactivity would dampen responses to IFN, which was clearly not the case. The coinhibitory receptors PD1 and CTLA4 are overexpressed in Treg cells, and some reports have suggested an effect of CTLA4 on signal transduction (46), but this was not observed in our experimental system, where adventitious effects of generalized inflammation due to the mutations were avoided by the mixed chimera context.…”

Section: Discussionmentioning

confidence: 99%

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Yan

Farache

Mingueneau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

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Section: Discussionmentioning

confidence: 99%

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Yan

Farache

Mingueneau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…SOCS1 negatively controls the signaling of many cytokines besides IFN-γ, such as IL-12 and IL-2 in turn regulating T cell responses [34,35]. Moreover, SOCS1 expression is necessary for the suppressor function of T regs cells in vivo by maintaining FoxP3 expression and hampering IFN-γ and IL-17 production in vivo [36]. T regs cells are in fact increased in active TB [37], and the experimental Suppressed Th1 immune responses have been shown to be associated with TB in vitro and poor clinical outcome [39].…”

Section: Discussionmentioning

confidence: 99%

Differential Early Secreted Antigen Target (ESAT) 6 kDa–induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis

Masood

Hussain

Rao

et al. 2014

J Infect Dev Ctries

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Introduction: Expression of Suppressor of cytokine signaling (SOCS)-1 molecules is increased in patients with tuberculosis (TB). Early Secreted Antigen Target (ESAT)-6 kDa -induced IFN-γ responses indicate Mycobacterium tuberculosis infection. The effect of ESAT6-stimulation on SOCS1 in the host is not known. Methodology: Healthy asymptomatic controls had a negative (n = 16) or a positive ( n = 13) tuberculin skin test (TST). ESAT6-induced IFN-γ responses classified these controls as positive (EC ESAT6 IFN-γ (+), n = 5) or negative (EC ESAT6 IFN-γ (-), n = 24) responders. Patients had pulmonary (n = 21) or extra-pulmonary (n = 30) tuberculosis. Peripheral blood cells were stimulated with ESAT6 and mRNA expression of IFN-γ and SOCS1 was determined. Results: ESAT6-induced IFN-γ expression was raised in EC ESAT6 IFN-γ (+) as compared with EC ESAT6 IFN-γ (-), p = 0.019. ESAT6-induced SOCS1 mRNA expression was increased in both pulmonary TB and extra-pulmonary TB patients as compared with both EC groups. ESAT6-induced IFN-γ/SOCS1 mRNA expression ratio was decreased in TB patients as compared with both EC groups. Conclusion: M. tuberculosis infection induces increased ESAT6-induced IFN-γ responses in both latent and active TB. Our data shows down-regulation of IFN-γ / SOCS1 expression to be induced only in active TB cases, distinguishing them from healthy individuals likely to have latent TB. A decreasing IFN-γ /SOCS1 ratio may leads to reduced Th1 immunity which contributes to inability of the host to control clinical disease.

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“…As Stat1 signalling is responsible for turning on T-bet expression in response to IFNg, it is likely that attenuated Stat1 allows Tregs to turn on lower levels of T-bet and gain the chemotactic capacity of Th1 cells, without actually differentiating into the Th1 lineage. Thus, loss of miR146a or SOCS1 in Treg results in excessive T-bet expression and differentiation of Tregs into IFNg-producing Th1 cells [22,23]. This Treg dedifferentiation has also been demonstrated during heavy Th1 responses against Toxoplasma gondii infection, where Treg produce IFN-g and contribute to the Th1 response [24] and in human Treg co-cultured with high numbers of allogeneic B cells in vitro, where Treg promote rather than inhibit effector T cell responses [25].…”

Section: Stability Mechanisms Limit the Effect Of T-bet Expression Inmentioning

confidence: 94%

“…For T-bet þ Tregs, we have some data on how T-bet expression in Tregs drives CXCR3 expression, while induction of IFNg is kept low: unlike effector T cells where T-bet expression leads to high IFNg production and Th1 differentiation. This resistance is mediated by expression of SOCS1 and the microRNA miR-146a, which decreases Stat1 signalling and expression, respectively [22,23]. As Stat1 signalling is responsible for turning on T-bet expression in response to IFNg, it is likely that attenuated Stat1 allows Tregs to turn on lower levels of T-bet and gain the chemotactic capacity of Th1 cells, without actually differentiating into the Th1 lineage.…”

Section: Stability Mechanisms Limit the Effect Of T-bet Expression Inmentioning

confidence: 99%

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

2012

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The potential for self‐reactive T cells to cause autoimmune disease is held in check by Foxp3+ regulatory T cells (Tregs), essential mediators of peripheral immunological tolerance. Tregs have the capacity to suppress multiple branches of the immune system, tightly controlling the different subsets of effector T cells across multiple different tissue environments. Recent genetic experiments have found mutations that disrupt specific Treg: effector T cell relationships, leading to the possibility that subsets of Tregs are required to suppress each subset of effector T cells. Here we review the environmental factors and mechanisms that allow Tregs to suppress specific subsets of effector T cells, and find that a parsimonious explanation of the genetic data can be made without invoking Treg subsets. Instead, Tregs show a functional and chemotactic plasticity based on microenvironmental influences that allows the common pool of cells to suppress multiple distinct immune responses.

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SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Abstract: SOCS1 is required to restrict IFN-γ and IL-17 expression and maintain Foxp3 expression in and function of regulatory T cells.

Cited by 172 publications

References 47 publications

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Differential Early Secreted Antigen Target (ESAT) 6 kDa–induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

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