CD4+ regulatory T cells control Th17 responses in a Stat3-dependent manner

By A. Chaudhry, D. Rudra, P. Treuting, Robert Samstein, Yuqiong Liang, A. Kas, Alexander Y. Rudensky. Science, 2009

1,037 citations recorded by the source corpus.

Outfoxing Immune Excess Immune responses are kept in check by Foxp3-expressing CD4+-regulatory T cells (Tregs) through a variety of mechanisms. Expression of specific transcription factors directs Treg responses into distinct T helper cell lineages; however, the transcription factors that regulate particular helper lineages have not been completely characterized. Chaudhry et al. (p. 986, published online 1 October) show that the transcription factor Stat3, that is required for the initial differentiation of TH17-effector T cells, is also required for Treg cell-mediated suppression of TH17-mediated immune responses. Mice carrying a Treg cellspecific deletion in Stat3 succumb to an intestinal inflammatory disease driven by uncontrolled TH17 responses. Thus, different classes of immune responses can result from the expression of helper lineage–specific transcription factors. Suppressor T cells regulate different classes of immune responses through induction of specific transcription factors. Distinct classes of protective immunity are guided by activation of STAT transcription factor 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 transcription factor 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/941abafbf3b6f6b7216be3ef5208b4c14afecb4a

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Citations in the corpus

Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, neutral): “Likewise, we have found that Treg cell-restricted ablation of Stat3, a transcription factor required for Th17 induction, leads to uncontrolled Th17-dependent pathology (Chaudhry et al., 2009).”
Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation (2011, positive): “Recently, we demonstrated that expression of STAT3 in Treg cells is a prerequisite for their ability to suppress Th17 cell responses and that ablation of STAT3 in Treg cells results in fatal Th17 cell-mediated colitis (Chaudhry et al., 2009).”
Chemokines and chemokine receptors: positioning cells for host defense and immunity. (2014, background): “Stat3 is a transcription factor associated with Th17 responses, and Stat3-deficient Tregs have reduced CCR6 expression (248).”
CXCR3 in T cell function (2011, background): “T-bet-expressing Foxp3+ Tregs specifically suppress Th1 inflammation, and not Th2- or Th17-driven inflammation, which have separately been shown to be suppressed by IRF4expressing and Stat3-expressing Tregs, respectively [59,60].”
The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells (2011, background): “In an analogous manner, the transcription factors T-bet and STAT3 control the homeostasis and function of T reg cells during T H 1 and T H 17 inflammation, respectivel”
Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. (2019, background): “(Buonocore et al., 2010; Chaudhry et al., 2009) functions of IL-17A and IL-17F individually have been reported, with evidence that blockade of both IL-17A and IL-17F is required to”
Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012, background): “Moreover, expression of STAT3 (which drives Th17 differentiation) in Tregs was increased and crucial during control of Th17-mediated intestinal pathology (Chaudhry et al., 2009).”
Differentiation of Effector CD4 T Cell Populations (2010, neutral): “STAT3—STAT3 is activated by IL-6, IL-21, and IL-23, cytokines that are involved in Th17 cell differentiation, amplification, and maintenance (21–24, 41, 42).”
Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors (2010, background): “Treg-specific deletion of Stat3 results in loss of the capacity of these Tregs to suppress Th17related autoimmune diseases (179); however, whether STAT3 is responsible for upregulating RORct and whether deletion of RORct from Tregs will also induce Th17-mediated diseases are not certain.”
Treg cells expressing the co-inhibitory molecule TIGIT selectively inhibit pro-inflammatory Th1 and Th17 cell responses (2014, background): “TIGIT Treg Cells Share Features with Proinflammatory T Cell Lineages Treg cells share a number of features with the effector population they suppress, including the expression of chemokine receptors as well as the transcription factors that induce the development of those effector T cells (Chaudhry ”