Mechanisms Controlling Regulatory T cell Effector Function in IBD

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PROJECT SUMMARY Mechanisms Controlling Regulatory T Cell Effector Function in IBD. The pathogenesis of inflammatory bowel disease (IBD) is characterized by immune dysregulation to components of the enteric microbiota. Findings from mouse models of IBD and recent human genetic studies highlight a critical, non-redundant role for the immunoregulatory cytokine IL-10 in the maintenance of intestinal immune homeostasis. Our lab has shown that Foxp3+ regulatory T (Treg) cells are, overwhelmingly, the major source of IL-10 in the intestines. However, IL-10 is only produced by a subset of Treg cells—defined as ‘effector’ (e)Treg cells. In preliminary studies that used an IL-10 transgenic reporter mouse model to explore differences between transcriptomes of T cells separated on the basis of expression of IL-10, we identified the DNA-binding factor Gfi1 as a central repressor of Il10 gene expression in all subsets of CD4 T cells, including Treg cells. Gfi1 appears to act both directly, via interactions with the Il10 locus, and indirectly, by repressing transcription of Prdm1 (Blimp1), which is a trans-activator of Il10 in Treg cells. Additionally, Gfi1 represses other genes that appear to be central to eTreg function, suggesting that Gfi1 may play a key role in regulating the differentiation of eTreg cells. Finally, we have identified cytokine signals that induce the expression of IL-10 by Foxp3+ Treg cells. In essence, IL-10 expression by Treg cells is Iatent and requires activating cytokine signals that repress Gfi1 to derepress transcription of Il10 as part of eTreg cell programming. This could explain why IL-10 expression by T cells is largely restricted to the intestines at homeostasis, where on-going responses to the microbiota provide a state of controlled inflammation and a source of pro-inflammatory cytokines that promote the development of IL-10– expressing eTreg cells. We hypothesize that inflammatory signals in the gut override Gfi1-mediated repression of eTreg cell development and that modulation of Gfi1 expression will impact the protective capabilities of Treg cells in an inflammatory environment—in large part through modulation of IL-10 expression. Further, we posit that Gfi1 maintains a pathogenic phenotype in CD4 T effector cells by repressing IL-10, such that inhibition of Gfi1 will convert pathogenic T cells to IL-10–producing protective T cells, thereby ameliorating intestinal disease. Herein, we will define mechanisms by which Gfi1 represses IL-10 in murine and human Treg cells and we will perform proof-of-principle studies to examine the impact on IBD pathogenesis of dysregulated expression of Gfi1 by T cells. The delineation of mechanisms by which cytokines modulate the Gfi1–Blimp1 axis to control IL-10 expression by T cells will lead to a better understanding of homeostatic networks that prevent IBD, and will provide a basis for discovery of novel therapeutic approaches by which endogenous IL- 10 can be up-regulated, and the differentiation and function of eTreg cells enhanced, to treat IBD.