GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice

Abstract

Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation.

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

“…It was interesting to see that the different expression patterns of CCR6 and CXCR3 showed orthogonal patterns of expression in RORC, TBX21, and GATA3. In addition, there was a similar pattern of expression between GATA3 and FOXP3, consistent with the role of GATA3 on FOXP3 expression (23,24).…”

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

“…12 Similarly, the Th2-associated transcription factor GATA3 was found to play an important role for Treg function, as it was shown that GATA3-deficient Tregs display profound defects in peripheral homeostasis and suppressive function. 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.…”

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

“…The transcription factor Foxp3 plays a crucial role in immune homeostasis and T reg development (34)(35)(36), as demonstrated by the dramatic autoimmune phenotype of the Foxp3 forkhead domain-deficient Scurfy mouse (37), and autoimmune disease in humans bearing Foxp3 mutations known as immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. Foxp3 expression itself is regulated by cooperative activation of multiple transcription factors by cytokine receptors, including the TGF-β receptor (26,(38)(39)(40)(41). Specifically, TGF-β receptor binding causes the transcription factors Smad3 and nuclear factor of activated T cells (NFAT) to promote Foxp3 expression through histone acetylation at one of two known enhancer elements (26).…”