Gene Regulatory Networks Controlling Effector and Regulatory T Cell Balance in IBD

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PROJECT SUMMARY Gene Regulatory Networks Controlling Effector and Regulatory T Cell Balance in IBD. The pathogenesis of inflammatory bowel disease (IBD) is characterized by immune dysregulation to components of the enteric microbiota. Studies from mouse models of IBD and recent genetic data from humans highlight a critical, non-redundant role for the immunomodulatory cytokine IL-10 in the maintenance of intestinal immune homeostasis. Although the essential regulatory function of IL-10 is well established, molecular mechanisms that control expression of the gene that encodes IL-10 are not well understood. This is particularly the case for Foxp3+ regulatory T cells, the principal source of immunoregulatory IL-10 in the intestines. In studies that have 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 recently identified the transcriptional factor, Gfi1, as a central repressor of IL-10 expression in CD4 T cells. This represents the first identification of a transcriptional repressor of Il10 gene expression, and suggests that recruitment of Gfi1 to the Il10 locus or other gene loci inhibits the expression of IL-10 through mechanisms yet to be fully defined. Importantly, we have found that Gfi1 functions as a pan-repressor of Il10 gene expression in all CD4 T cell subsets, but specifics of the mechanism by which it exerts its actions are subset- specific. Specifically, preliminary findings indicate that in Foxp3+ Treg cells there is use of a Gfi1-Blimp1 transcriptional network that controls production of IL-10. Moreover, we have identified cytokine signals that induce the expression of IL-10 in Foxp3+ Treg cells. In essence, we find that IL-10 expression by Treg cells is Iatent, and requires activating cytokine signals that repress Gfi1 to derepress IL-10 expression. This would 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 development of “effector,” or IL-10–expressing Treg cells. We hypothesize that inflammatory signals in the gut can override Gfi1-mediated IL-10 repression in Foxp3+ regulatory cells and that modulation of Gfi1 expression will impact the protective capabilities of Tregs in an inflammatory environment. Further, we hypothesize that during intestinal inflammation, Gfi1 maintains a pathogenic phenotype in CD4 T effector cells by suppressing IL-10 expression and importantly, that inhibition of Gfi1 expression in colitic T cells will convert pathogenic cells to IL-10–producing protective cells, thereby ameliorating intestinal disease. Herein, we will define mechanisms by which Gfi1 represses expression of IL-10 in mouse and human Treg cells and will perform proof-of-principle studies that examine the impact of Gfi1 dysregulation in T cells on IBD pathogenesis. Delineating the interplay of extrinsic cytokine signals with the cell-intrinsic Gfi1 and Blimp1 axis to control IL-10 expression by intestinal Treg cells has important implications for understanding homeostatic networks that prevent IBD and offers novel approaches to de-repress IL-10 as a therapeutic strategy.