Inflammatory bowel disease T-cell receptor (TCR) specificity driven by HLA-DRB1 is associated with shared antigen targets and distinct memory CD4+ T-cell signatures across ulcerative colitis and Crohn’s disease. The findings highlight how genetic risk contributes to shaping patterns of immune recognition in inflammatory bowel disease (IBD) and may underpin shared inflammatory pathways across disease phenotypes.
HLA-DRB1-driven T cell signatures in inflammatory bowel disease (IBD).
The researchers genotyped HLA-DRB1 and identified 3.13 million TCR beta sequences derived from circulating memory CD4+ T cells in 33 patients with inflammatory bowel disease, including 20 with ulcerative colitis and 13 with Crohn’s disease, along with 14 healthy controls. Using the GLIPH2 algorithm, 468,441 candidate sequences based on CDR3 amino acid polymorphisms were clustered into 440 high-confidence TCR specificity clusters. These clusters were significantly enriched among individuals sharing HLA-DRB1 alleles, suggesting a strong genetic influence on TCR specificity in inflammatory bowel disease (IBD).
Common antigen specificity clusters in IBD
Within IBD, five TCR specificity clusters were enriched in patients and shared between ulcerative colitis and Crohn’s disease. This convergence suggests that common antigenic targets may contribute to immune activation across different clinical subtypes of IBD, despite heterogeneity in affected areas of the GI tract. The presence of overlapping specificity groups suggests that selection pressures associated with HLA-DRB1 may shape a unified antigen-driven immune response in inflammatory bowel disease (IBD).
Expansion of cytotoxic T cells in inflammatory bowel disease
IBD-associated immune profiling has also shown increased frequencies of GZMB+PRF1+CD4+ cytotoxic cells and KIR+CD8+ T cells in a subset of individuals carrying risk alleles. These expansions suggest that specific genetic backgrounds in inflammatory bowel disease (IBD) may promote cytotoxic immune programs alongside specific TCR specificity signatures.
Overall, the TCR specificity associated with HLA-DRB1 provides mechanistic insight into how genetic susceptibility shapes antigen recognition and effector T cell activity in inflammatory bowel disease (IBD). These data support the existence of shared immune pathways across ulcerative colitis and Crohn’s disease and may contribute to future antigen discovery and personalized therapeutic approaches in IBD.
reference
Chan J et al. CD4+ T-cell receptor specificity clusters shared in Crohn’s disease and ulcerative colitis. JCI Insight. 2026; doi: 10.1172/jci.insight.195354.
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