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. Recent studies have revealed that the innate immune system includes functional counterparts of T helper (Th) cells, which 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), have also been implicated in the pathogenesis of several autoimmune diseases, including inflammatory bowel disease (IBD). In discovery-driven profiling studies supported by an R21, the Co-PIs have recently defined the regulatory landscapes of Th-ILC counterparts derived from inflamed human mucosae, revealing collections of conventional- and super-enhancers that may control the expression of key immune mediators. Moreover, many enhancers that were active in specific ILC or Th subsets co-localized with autoimmune-associated disease SNPs, suggesting the regulatory elements may be important for controlling expression levels of nearby genes that mediate autoimmune pathogenesis. Despite this progress, the precise role of these potentially important regulatory elements in cell type-, agonist-, and disease-specific gene expression remains untested. The goal of the current project is to address these outstanding issues, focusing on regulation of the IL22-IL23R-IL1R1-STAT3 axis, which is critical for immune function of ILC3-Th17 counterparts and whose genetic loci are rich in autoimmune-associated SNPs. The Co- PIs will also define and test key aspects of the ILC3 regulome that control their functional conversion to ILC1, a process implicated in IBD pathogenesis. To achieve these goals, we will leverage the Co-PIs' complementary expertise. Dr. Colonna's lab discovered several ILC subsets and contributed to our understanding of their biology in mice and humans. Dr. Oltz's lab studies cis-regulatory circuits that drive lymphocyte development and transformation.
Three specific aims are proposed to test the hypotheses that: (i) unique sets of enhancers are critical for cell type- and agonist-specific expression of IL22 and IFNG in vivo, (ii) a subset of disease- associated SNPs disrupts transcription factor binding and enhancer function to alter IL23R, STAT3, or IL1R expression in ILC3 and Th17 cells during autoimmune pathogenesis, and (iii) ILC3?ILC1 conversion requires full activation of ILC1-associated enhancers that remain poised in ILC3 and, conversely, a decommissioning of ILC3-specific enhancers, perhaps converting them to a repressed state. Together, our project will identify key features of the ILC-Th regulomes that dominate expression patterns of genes involved in autoimmune inflammation, providing insights into independent roles of cytokine expressing cells in pathogenesis, ultimately opening new therapeutic avenues.

Public Health Relevance

The immune system strikes a delicate balance between pathogen elimination and protection of host tissue from damage incurred by inflammation during an immune response. Maintaining this balance requires rapid communication between cells of the innate and adaptive immune system and, when disrupted, can produce widespread damage that characterizes many autoimmune conditions. The proposed study will define the regulatory logic driving expression programs for key genes that help establish this cost?benefit balance in specific subsets of innate and adaptive lymphoid cells implicated in inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Rothermel, Annette L
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Washington University
Schools of Medicine
Saint Louis
United States
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Barrow, Alexander David; Colonna, Marco (2018) Innate lymphoid cell sensing of tissue vitality. Curr Opin Immunol 56:82-93