Cis-Regulatory Circuits for ILC Function and Plasticity

PROJECT SUMMARY A delicate regulatory balance must be achieved in cells of the innate and adaptive immune systems to effectively eliminate pathogens, while minimizing damage in neighboring tissues. Defects in regulatory mechanisms that govern expression of cellular or soluble mediators can interfere with pathogen clearance or lead to unchecked inflammatory responses associated with autoimmunity. We now appreciate that the innate immune system includes functional counterparts of T helper (Th) cells, but the innate cells lack antigen-specific receptors and respond with enhanced kinetics and vigor to danger signals induced by pathogenic insults. The Th counterparts, called innate lymphoid cells (ILCs), also have been implicated in the pathogenesis of several autoimmune diseases, including inflammatory bowel disease (IBD). In discovery-driven profiling studies, the MPIs have defined chromatin landscapes of Th-ILC counterparts derived from human mucosae, revealing collections of regulatory elements (REs) that may control the expression of key immune mediators. Moreover, many REs that were active in specific ILC or Th subsets co-localized with disease-associated SNPs, and are conserved in mice, suggesting they may be important for controlling expression levels of nearby genes in inflammation-driven pathogenesis. Indeed, the MPIs have defined novel functions for two such REs in controlling expression of a signature cytokine (IL-22) and a gene required for effector functions in most lymphoid cells (Tcf7). Despite this progress, the roles of potentially important REs in cell type-, agonist-, and disease-specific gene expression largely remain untested. The goal of the current project is to address these outstanding issues, focusing on regulation of a broad panel of signature genes that control ILC-Th function. To achieve these goals, we will leverage the MPIs’ complementary expertise. Dr. Colonna’s lab discovered several ILC subsets and continues to contribute to our understanding of their biology in mice and humans. Dr. Oltz’s lab studies cis-regulatory circuits that drive lymphocyte development and transformation. Two specific aims are proposed to test the hypotheses that: (i) unique sets of REs are critical for cell type- and agonist- specific expression of ILC3-Th17/22 cell signature genes in health and disease, (ii) the transcription factors ZFP683 and PRDM1 orchestrate key aspects of regulomes that govern the biology of natural killer (NK) cells and their ILC1 counterparts. Continuation of our productive collaboration will identify and functionally test critical players – both REs and transcription factors – that dominantly regulate expression patterns of genes involved in inflammatory diseases, providing insights into independent roles of cytokine expressing cells in pathogenesis, and ultimately opening new therapeutic avenues.