Shared CD4+ T cell receptor specificity groups in Crohn’s disease and ulcerative colitis
Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis
Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis
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Research Article Gastroenterology Immunology

Shared CD4+ T cell receptor specificity groups in Crohn’s disease and ulcerative colitis

Abstract

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is marked by chronic intestinal inflammation and dysregulated immunity. Although UC and CD affect different areas of the gastrointestinal tract, both diseases share aberrant CD4+ memory T cell responses, with HLA-DRB1 as a major genetic risk factor. HLA-DRB1 encodes MHC class II molecules that influence the CD4+ T cell receptor (TCR) repertoire, yet how these genotypes shape TCR specificity in IBD remains unclear. Here, we genotyped HLA-DRB1 and profiled 3.13 million TCRβ sequences from circulating memory CD4+ T cells in 33 IBD patients (20 UC, 13 CD) and 14 healthy controls. Using the GLIPH2 algorithm, we distilled 468,441 candidates based on CDR3 amino acid motifs into 440 high-confidence TCR specificity groups significantly enriched among individuals sharing HLA-DRB1 alleles. Notably, 5 specificity groups were IBD-enriched and were shared between UC and CD, suggesting common antigen targets in both diseases. We also observed increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+CD8+ T cells in a subset of risk-allele carriers with IBD. These findings elucidate distinct, HLA-linked TCR specificity groups in IBD and provide mechanistic insights that may advance antigen discovery and personalized medicine.

Authors

Joshua E. Chan, Azam Mohsin, Jens Krijgsman, Ciska Lindelauf, Qinghui Mu, Brianna Cavalla, Xuhuai Ji, Sarah E. Streett, Vincent van Unen, Mark M. Davis

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Figure 1

GLIPH2 to prioritize IBD-associated TCR specificity groups.

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GLIPH2 to prioritize IBD-associated TCR specificity groups. (A) Pie char...
(A) Pie charts illustrating the distribution of HLA-DRB1 alleles per risk group in the cohort (healthy controls, n = 14; UC, n = 20; and CD, n = 13). (B) GLIPH2 filtering workflow of our cohort’s TCRs, yielding 5 significantly IBD-enriched and 10 significantly healthy-enriched specificity groups. Memory repertoire enrichment score was determined with a Fisher’s test against reference naive CD4+ T cell repertoire datasets. (C) Four hundred forty specificity groups were obtained after standard GLIPH2 filtering; those significantly enriched in either healthy controls or IBD patients are shown in red. On the left side of the graph (log2 fold change < 0) are the specificity groups enriched in TCRs from healthy controls, and on the right (log2 fold change > 0) are specificity groups enriched in TCRs from IBD patients. (D) Dominant HLA-II allele in healthy-enriched and IBD-enriched TCR specificity groups. In parentheses are the numbers of patients who bear each HLA-II allele. (E) Enrichment of our study’s 5 IBD-enriched specificity groups, in an external, European dataset of 32 IBD patients and 24 healthy controls. (F) Distribution of memory CD4+ TCRs, stratified by disease state (remission vs. active) and subtype (CD vs. UC), that constitute each IBD-enriched specificity group. (G) Percentage of TCRs in active and remission CD and UC specificity groups.