A predisposing effect of HLA class II genes in celiac disease by skewing the naive CD4+ T-cell receptor repertoire
Lindeman, I.; Officer, A.; Dahal-Koirala, S.; Risnes, L. F.; Hjort, R.; Lundin, K. E. A.; Ness-Jensen, E.; Watson, C. T.; Sollid, L. M.
Show abstract
Polymorphisms of human leukocyte antigen (HLA) genes confer risks for many human diseases. For predisposing effects relating to T-cell receptor (TCR) recognition of peptide-HLA, the effect can be both selection of the TCR repertoire and preferential presentation of disease-driving epitopes. In celiac disease (CeD) HLA-DQ2.5 predisposes by presenting deamidated gluten peptides to CD4+ T cells that typically employ stereotyped TCRs. Here we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the {beta} TCR repertoires of naive CD4+ T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4+ TCR repertoire was significantly affected by HLA and TRA and TRB polymorphisms. Individuals carrying the HLA-DQ2.5 allotype exhibited increased frequencies of TCR genes involved in stereotyped recognition of gluten epitopes thus demonstrating a disease-predisposing effect of HLA by selection of a disease-relevant TCR repertoire.
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