CHROMATIN-BASED DISCOVERY OF ILC GENE REGULATORY CIRCUITS

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Productive elimination of pathogens while minimizing damage to neighboring tissues requires facile communication between cells of the innate and adaptive immune systems. Defects in cellular or soluble components of these communication networks can interfere with pathogen clearance or lead to unchecked inflammatory responses and incumbent tissue damage associated with autoimmunity. In many tissues, pathogenic insult triggers antigen-presenting cells to secrete cytokines that are initially translated by innate lymphoid cells (ILC). In turn, activated ILC subsets secrete signature cytokines, which promote the release of antimicrobial peptides, minimize damage to surrounding cells, and influence the balance of T helper lymphocytes. Emerging evidence suggests that efficient communication during an immune response relies on the presence of cellular homologues, which mediate innate versus adaptive arms of the response. For example, ILC3 are innate immune cells that secrete IL-22 in response to IL-23, promoting elimination of extracellular pathogens and fungi. Their counterparts from the adaptive immune system, Th17 and Th22, express IL-22 in response to activation of their antigen receptor (TCR). The ILC3-Th17-Th22 cohort all develop from common progenitors and share requirements for some transcription factors, but are clearly distinct in function (only Th17/22 express IL-17) and mechanisms of activation (cytokine versus TCR). Elucidation of the developmental relationships between these immune subsets and their functional plasticity remains an important goal in immunology. Resolution of these issues requires a deeper understanding of transcriptional and regulatory programs employed by each subset in their basal and activated states. The applicants' laboratories will leverage their complementary sets of expertise to solve this problem, leading them previously to the discovery of ILC subsets and immune function, as well as chromatin-based identification of gene regulatory circuits in lymphoid cells. The current project aims to dissect whether human ILC3 and Th17/22 employ a combination of overlapping and divergent regulatory elements to express shared genes (e.g., IL-22) in response to distinct cues (cytokines versus antigen receptors), while simultaneously activating signature expression programs (e.g., IL-17) that mediate unique functions of innate or adaptive immunity. Experiments are proposed to (i) isolate human ILC3, Th17/22, and naïve counterparts from distinct microenvironments (tonsil and blood), (ii) map transcriptional and regulatory landscapes of these cells in their basal and activated states, (iii) decipher the regulatory logic for each subset by connecting cis-elements to target genes, and (iv) employ circuit diagrams to establish developmental relationships, functional work-scopes, and plasticity between three related cell types that are critical for elimination of extracellular pathogens. These studies will provide regulatory blueprints for the ILC3 gene expression program, which strikes a homeostatic balance during immune responses to pathogens; keeping inflammation, tissue damage, and oncogenesis in check.