CD4 ⁺ Regulatory T Cells Control T _H 17 Responses in a Stat3-Dependent Manner

Abstract

Distinct classes of protective immunity are guided by activation of STAT transcription factor (TF) family members in response to environmental cues. CD4+ regulatory T cells (Tregs) suppress excessive immune responses, and their deficiency results in a lethal, multi-organ autoimmune syndrome characterized by T helper 1 (Th1) and T helper 2 (Th2) CD4+ T cell-dominated lesions. Here we show that pathogenic Th17 responses in mice are also restrained by Tregs. This suppression was lost upon Treg-specific ablation of Stat3, a TF critical for Th17 differentiation, and resulted in the development of a fatal intestinal inflammation. These findings suggest that Tregs adapt to their environment by engaging distinct effector response-specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response.

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

“…However, it is not clear whether such Treg cells have intrinsically different suppressive function or whether they share common suppressive properties and the specificity is exerted mainly through local environmental adaptation. The latter hypothesis is supported by the observations that Treg cells isolated from these studies largely show intact suppressive activity in vitro (9)(10)(11)(12). We sought to approach this question by addressing whether transcriptionally diverse Treg cell subsets exist in humans, and whether the diversity accounts for potential differences in their in vitro functionality.…”

“…Several key studies have revealed a biased breakdown of tolerance when Treg cells are genetically mutated for particular genes. Specifically, Tregspecific deletion of T-bet, IFN regulatory factor 4, Stat3, and Bcl6 resulted in the impairment of specific regulation of Th1, Th2, Th17, and T follicular helper cells, respectively (9)(10)(11)(12). The finding that the key transcription factors for Th cell differentiation are also required for Treg cells to suppress these Teff cells suggests that the Treg population comprises multiple functional subsets, some of which may have a designated Th cell target.…”

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…However, all animals have naturally occurring Treg (nTreg) cells that confer basal suppression of effector cell functions; the depletion of nTreg cells results in the induction of autoimmune and/or inflammatory diseases, which are associated with enhanced autoreactive cellular immune responses (61). Therefore, it is common that total Treg cell depletion in mice results in stronger cellular immune responses than do those in Treg cell-competent mice, and this could be observed with any kind of infection (62,63). A strategy to deplete virus-induced Treg cells alone, without affecting the numbers and functions of nTreg cells, would be necessary to precisely determine the role of induced Treg cells in vivo, which has never been demonstrated.…”

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…13,14 In addition, Treg-specific deletion of the transcription factors IRF4 (interferon regulatory factor 4) or STAT3 (signal transducer and activator of transcription 3) resulted in an impaired regulation of Th2-and Th17-dominated immune responses, respectively. 15,16 Recently, a population of germinal center-resident Tregs, termed follicular regulatory T cells, was identified. 17,18 These follicular regulatory T cells suppress germinal center B and T cells and depend, similar to their follicular T helper cell counterparts, on the expression of the transcription factor Bcl6 for their development.…”