High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells...

Innate lymphoid cells (ILCs) are rare tissue-resident lymphocytes that functionally mirror cells of CD4⁺ T helper lineage but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched at barrier sites, regulating inflammation and promoting tissue integrity. Here we profile the promoter-anchored chromosomal contacts of primary human ILC3s using low-input, high-resolution targeted chromosome conformation capture and compare them with those in CD4⁺ T cells. We use these data to link Crohn's disease genome-wide association study variants with target genes, implicating both known and unanticipated candidates, including CLN3, a causal gene for Batten disease. We show that Cln3 overexpression in a mouse ILC3-like cell line alters stimulation-induced transcriptional programs and cytokine secretion. Extending our approach to five additional immune genome-wide association study traits reveals enrichment for regulators of ILC3 activation. Our work develops methods, maps long-range gene regulation in ILC3s, and prioritizes immune disease risk genes with roles in this clinically relevant immune cell type.