Antigen-driven expansion of public clonal T cell populations in inflammatory bowel diseases

Background Inflammatory Bowel Diseases (IBDs), including Crohn's disease (CD) and Ulcerative colitis (UC) are known to involve shifts in the T cell repertoires of affected individuals. These include a reduction in regulatory T cells in both diseases, increase in TNF-alpha production in CD, expansion of an unconventional T cell population in CD, and clonal expansion of abundant T cell populations in CD mucosal tissue. There are also differential HLA risk and protective alleles between CD and UC, implying CD- and UC-specific repertoire changes that have not yet been identified. Methods We performed ImmunoSequencing on blood samples from 3,853 CD cases, 1,803 UC cases, and 5,596 healthy controls. For each sample we imputed HLA type and cytomegalovirus (CMV) infection status based on public T cell receptor β (TCRB) usage and identified public TCRBs enriched in CD or UC cases. Findings We find that there is a CMV-dependent increase in T cell clonality in CD and UC cases compared to CMV positive controls, and a CMV-independent decrease in low-expansion clonal populations in CD only. Strikingly, from blood we identify public TCRBs specifically expanded in CD or UC. These sequences are more abundant in intestinal mucosal samples, form groups of similar CDR3 sequences, and can be associated to specific HLA alleles. Although the prevalence of these sequences is higher in ileal and ileocolonic CD than colonic CD or UC, the TCRB sequences themselves are shared across CD and not with UC. Interpretation There are peptide antigens that commonly evoke immune reactions in IBD cases and rarely in non-IBD controls. These antigens differ between CD and UC. CD, particularly ileal CD, also seems to involve more substantial changes in clonal population structure than UC, compared to healthy controls. ### Competing Interest Statement M Pesesky, R Bharanikumar, C Carty, N Singh, MG Noceda, RM Gittelman, D May, JN Dines, W Zhou, IM Kaplan, TM Snyder, H Chen-Harris, B Howie, and HS Robins have or had employment and equity ownership with Adaptive Biotechnologies. H Zahid has or had employment and equity ownership with Microsoft Research.