The dynamic role of HLA proteins on compositional alterations of T-cell repertoires in inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD), which is characterised by genetic predispositions and dysregulated immune responses, is rapidly emerging as a global health challenge. Genetic variations in the human leukocyte antigen (HLA) region are strongly associated with IBD; nonetheless, the functional consequences of this variation on the composition of T-cell receptors remain poorly understood. MethodsWe conducted comprehensive CDR3-QTL mapping using T-cell receptor beta (TRB) repertoires paired with HLA allotypes from 1,973 individuals, including 1,201 individuals with IBD and 772 healthy controls (HCs), to explore the role of the HLA allelic variants on TRB composition. Using network analyses, we defined key CDR3 motifs of public clones that were linked to risk HLA alleles for chronic inflammatory diseases. ResultsWe identified novel sites within both HLA class I and class II proteins that were strongly linked to TRB amino acid composition - cdr3QTLs, in both HCs and individuals with IBD. Those sites in HLA-DRB1 and HLA-DQ had stronger effects on CDR3 composition than did the disease in the IBD cohort. In HCs, but not in UC or CD, the strongest HLA signals that affected expanded clones, overlapped with primary CD risk loci from GWAS, e.g., DRB1 site 70 and DQA1 site 25. The strongest CD-specific effects on TRB composition were found in HLA-B, especially at sites that modulate viral responses (e.g., HLA-B sites 9, 67). Finally, the main risk HLA alleles for chronic inflammatory diseases clustered together based on the physicochemical properties of residues mapped to cdr3QTLs, suggesting that risk alleles might exert similar effects on the TRB repertoire. ConclusionStructurally, the main cdr3QTLs in both HLA class I/II are located in peptide-binding sites or sites contacting TCRs, highlighting their direct and antigen-mediated influences on TRB repertoires. Our findings suggest that cdr3QTLs in HLA class I exert IBD-specific effects on the TRB composition, influencing the dysregulated T cell responses implicated in IBD pathogenesis, possibly on the earlier stages of T cell development. While HLA class II cdr3QTLs show universal effects and strong associations with T-cell receptors, irrespective of disease.