Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis

Abstract

Summary STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis, we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4+ T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4+ T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation, and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis.

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

“…In the case of the Il17a and Rorc gene loci, STAT3 directly binds the promoter and also intergenic regions and induces alterations to the epigenetic signature of these genes. Consistent with these studies (37,38), loss of STAT3 resulted in the disappearance of IL-17A-producing cells (Fig. S5A).…”

“…STAT3 directly regulates not only gene expression but also epigenetic modifications of numerous genes involved in Th17 cell differentiation (37,38). In the case of the Il17a and Rorc gene loci, STAT3 directly binds the promoter and also intergenic regions and induces alterations to the epigenetic signature of these genes.…”

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…HIC1 has been shown to interact with and inhibit DNA binding of transcription factors such as T-cell factor-4, b-catenin, and STAT3. [38][39][40] As HIC1-deficient T H 17 cells produce heightened levels of the STAT3 target gene IL-17A, 41 we hypothesized that increased STAT3 activity was associated with HIC1 deficiency. We first examined the levels of IL-6-induced active phosphorylated STAT3 in HIC1-sufficient and -deficient T H 17 cells by flow cytometry.…”

“…Consistent with this hypothesis, we found increased STAT3 binding to the Il17a promoter in the absence of HIC1 (Figure 8d), whereas there was no difference in binding at an irrelevant site (Il5 promoter). Examination of mRNA expression for other known STAT3 target genes associated with TH17-cell differentiation 41 revealed slight but insignificant increases in gene expression of Rorc, Socs3, Irf4, Ahr, or Il23r (Figure 8e). Thus, HIC1 does not appear to directly regulate the molecular machinery that Our results suggest that the micronutrient RA regulates HIC1 expression in immune cells in the intestine.…”

“…54 Further, STAT3 was shown to be required to drive both colitis and systemic inflammation not only by modulating T H 17-cell differentiation but also by promoting T-cell activation and survival. 41 However, targeted therapies against IL-17A in Crohn's disease have been proven ineffective 55,56 and recent studies have shown that IL-17A is important for maintaining intestinal barrier integrity and has a protective role in regard to the development of colitis. 57,58 Further, it is becoming more apparent that the T H 17-cell lineage has a degree of heterogeneity with regards to pathogenicity.…”