High-resolution promoter interaction analysis implicates genes involved in the activation of type 3 innate lymphoid cells in autoimmune disease risk

Innate lymphoid cells (ILCs) are rare, tissue-resident lymphocytes that functionally mirror CD4+ T helper lineages 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 Promoter Capture Hi-C (PCHi-C) and compare them with those in CD4+ T cells. We use these data to link Crohn’s disease genome-wide association study (GWAS) variants with target genes, detecting 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 programmes and cytokine secretion. Extending our approach to five additional autoimmune GWAS traits reveals enrichment for regulators of ILC3 activation. Our work develops new methods, maps long-range gene control in ILC3s and prioritises autoimmune disease risk genes with roles in this clinically relevant immune cell type.