IBD linked T cell receptor (TCR) specificity driven by HLA-DRB1 is associated with shared antigen targets and distinct CD4+ memory T cell signatures across ulcerative colitis and Crohn’s disease. The findings highlight how genetic risk contributes to shaping immune recognition patterns in IBD and may underpin shared inflammatory pathways across disease phenotypes. 

HLA-DRB1 Driven T Cell Signatures in IBD 

Researchers genotyped HLA-DRB1 and profiled 3.13 million TCR beta sequences derived from circulating memory CD4+ T cells in 33 patients with IBD, including 20 with ulcerative colitis and 13 with Crohn’s disease, alongside 14 healthy controls. Using the GLIPH2 algorithm, 468,441 candidate sequences based on CDR3 amino acid motifs were grouped into 440 high confidence TCR specificity groups. These groups were significantly enriched among individuals sharing HLA-DRB1 alleles, indicating a strong genetic influence on TCR specificity in IBD. 

Shared Antigen Specificity Groups In IBD 

Within IBD, five TCR specificity groups were enriched in patients and shared between ulcerative colitis and Crohn’s disease. This convergence suggests that common antigen targets may contribute to immune activation across different clinical subtypes of IBD, despite variation in affected regions of the gastrointestinal tract. The presence of overlapping specificity groups indicates that HLA-DRB1 linked selection pressures may shape a unified antigen driven immune response in IBD. 

Cytotoxic T Cell Expansion In IBD 

IBD linked immune profiling also demonstrated increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+ CD8+ T cells in a subset of individuals carrying risk alleles. These expansions suggest that specific genetic backgrounds in IBD may promote cytotoxic immune programmes alongside defined TCR specificity signatures. 

Overall, HLA-DRB1 linked TCR specificity provides mechanistic insight into how genetic susceptibility shapes antigen recognition and effector T cell activity in IBD. These data support the presence of shared immune pathways across ulcerative colitis and Crohn’s disease and may contribute to future antigen discovery and personalised therapeutic approaches in IBD. 

Reference 

Chan JE et al. Shared CD4+ T cell receptor specificity groups in Crohn’s disease and ulcerative colitis. JCI Insight. 2026; DOI: 10.1172/jci.insight.195354.  

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