# CIS-REGULATORY CIRCUITS FOR ILC FUNCTION AND PLASTICITY

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $639,023

## Abstract

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. 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 involv...

## Key facts

- **NIH application ID:** 10450007
- **Project number:** 5R01AI134035-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $639,023
- **Award type:** 5
- **Project period:** 2018-08-13 → 2025-01-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450007

## Citation

> US National Institutes of Health, RePORTER application 10450007, CIS-REGULATORY CIRCUITS FOR ILC FUNCTION AND PLASTICITY (5R01AI134035-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450007. Licensed CC0.

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