Regulating the Regulators: determinants of lineage- and tissue-specific Il10expression in CD4 +T cells

Abstract

Abstract IL-10 is an essential anti-inflammatory cytokine involved in mucosal immune regulation. Whereas many lineages of innate and adaptive immune cells can produce IL-10, a comprehensive understanding of the common, lineage-specific and tissue-specific regulatory mechanisms underlying Il10transcriptional regulation has remained elusive. Our lab recently identified the constitutive androstane receptor (CAR; encoded by Nr1i3)—a xenobiotic-sensing nuclear receptor (NR) with no previously known function in immune cells—as a selective regulator of Il10 gene expression in small intestinal (SI) type 1 regulatory (Tr1) cells. CAR induction of IL-10 expression in SI Tr1 cells stands in direct contrast with orthogonal mechanisms that underlie Il10gene regulation in large intestinal (LI) Foxp3+ T regulatory (Treg) cells, and that involve other nuclear receptors, such as vitamin D receptor (VDR). By using a combination of next-generation sequencing techniques (ATAC-seq, CITE-seq, ChIP-seq), I am assessing how, where and in which cell types CAR most prominently regulates Il10expression in vitroand in vivo. Our results are generating high resolution maps of Il10transcriptional regulatory networks that are differentially called upon in different cell types and discrete mucosal tissues to achieve the complex and dynamic regulation of Il10expression that is observed in vivo. Supported by grants from NIH (RO1 AI143821-03)