CD226 associates with interferon and inflammatory programs in intestinal γδ T and group 3 innate lymphoid cells in...

DNAM-1, encoded by CD226, is an activating immunoreceptor involved in lymphocyte function and tumor immunity, but its role in human inflammatory bowel disease remains poorly defined. Here, we examined CD226 expression and associated transcriptional programs across terminal-ileal immune cell populations using single-cell RNA-sequencing data from patients with Crohn's disease (CD) and healthy controls. CD226 transcripts were predominantly enriched in T-cell and innate lymphoid cell populations. In healthy controls, CD226 expression was primarily associated with metabolic and biosynthetic programs, whereas in CD it was strongly associated with interferon-related and inflammatory pathways, including TNF-NF-κB and IL-2-STAT5 signaling. These disease-associated associations were particularly evident in tissue-resident γδ T cells and group 3 innate lymphoid cells (ILC3s), where CD226 expression correlated with pro-inflammatory and effector programs. Thus, tissue-resident γδ T cells and ILC3s represent major cellular contexts in which CD226 is linked to inflammatory transcriptional programs in Crohn's disease, suggesting a potential role for DNAM-1 in intestinal mucosal inflammation.