The role of the transcription factor c-Maf in controlling mucosal inflammation in the intestine

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The intestinal immune system is constantly exposed to myriads of harmless and pathogenic microbes. Thus providing protective immunity and immunological tolerance at the same time represents a unique challenge for the mucosal immune system. CD4+ T cells orchestrate intestinal immune responses and deregulated T cell responses contribute to chronic inflammatory bowel disease (IBD). Interleukin-10 plays a central role for T cell-mediated intestinal immune regulation. It can be produced by regulatory T cells (Tregs) as well as by pro-inflammatory T cells as a potent self-limiting mechanism. Thus, therapeutic manipulation of IL-10 production by intestinal T cells represents an attractive opportunity to re-establish physiological tolerance in IBD patients. However, the regulation of IL-10 production by the various T cell subtypes is still not fully understood. We have previously identified the transcription factors Blimp-1 and c-Maf as central regulators of IL-10 production by pro-inflammatory Th1 cells. Our preliminary data now identify c-Maf as a unique transcription factor involved in intestinal regulation of T cell-mediated inflammatory responses at multiple levels. C-Maf is mainly expressed by intestinal regulatory (Treg) and conventional CD4+ T cell subsets and correlates with IL-10 production. T cell-specific c-Maf knockout almost abolished IL-10 production by all T cell subsets and led to increased expression of the inflammatory cytokines IL-17 and IFN-gamma by Foxp3- and Foxp3+ T cells. Interestingly c-Maf knockout mice also completely lack the RORgammat+ Treg subset in the intestine, which has recently been identified to be induced by microbiota in intestinal tissues. Thus c-Maf seems to play a broad and non-redundant role for the regulation of intestinal T cell homeostasis and immunity. Here we propose to further elucidate the role of c-Maf for the phenotype and function of intestinal CD4+ T cells and try to identify the signals and mechanisms regulating c-Maf expression. We will also address the transcriptional signature and the molecular mechanisms by which c-Maf promotes the immune-regulatory phenotype in different intestinal CD4+ T cell subsets. T cell- and Foxp3-specific c-Maf ko mice will be used to determine the role of c-Maf for pro-inflammatory and regulatory T cells in defined in vivo models of intestinal inflammation. In addition we will characterize c-Maf expression and function in human CD4+ T cell subsets employing our recently developed Antigen-Reactive-T cell Enrichment (ARTE)-technology allowing to isolate and characterize human inflammatory and regulatory T cells specific for intestinal antigens derived from blood and intestinal tissues. We propose that our project will help to define a central regulator of intestinal T cell homeostasis and tolerance in mouse and man, which will reveal new possibilities for specific therapeutic intervention in IBD.