Oral Presentation International Celiac Disease Symposium 2026

A predisposing effect of HLA class II genes in celiac disease by skewing the naive CD4+ T-cell receptor repertoire (146702)

Ida Lindeman 1 2 , Aengus Officer 2 , Shiva Dahal-Koirala 1 2 , Louise Fremgaard Risnes 1 2 , Rebecka Hjort 3 4 , Knut Lundin 1 2 , Eivind Ness-Jensen 3 4 5 , Corey T Watson 6 , Ludvig M Sollid 1 2
  1. Oslo University Hospital, Oslo
  2. University of Oslo, Oslo, OSLO, Norway
  3. University of Science and Technology, Trondheim and Levanger
  4. Levanger Hospital, Levanger
  5. Karolinska Institutet and Karolinska University Hospital, Stockholm
  6. University of Louisville, Louisville, KY

Background: Human leukocyte antigen (HLA) gene polymorphisms confer risk for many human diseases. Predisposing effects relating to T-cell receptor (TCR) recognition of peptide-HLA can involve both selection of the TCR repertoire and preferential presentation of disease-driving epitopes. In celiac disease (CeD) HLA-DQ2.5 predisposes through presentation of deamidated gluten peptides to CD4+ T cells with stereotyped TCRs. Whether HLA and/or TR germline variation predispose to CeD by imprinting the naive TCR repertoire is not understood.

Aim: To address whether genetic variants within the HLA and TR loci shape the naive TCR repertoire, and if such effects can predispose to CeD.

Materials and Methods: We bulk sequenced the αβ TCR repertoires of naive CD4+ T cells of 103 individuals with CeD and 103 controls, and genotyped single nucleotide polymorphisms within the TR and HLA regions. We then applied gene usage quantitative trait loci analyses to map genetic effects on the gene usage frequency of individual TRA and TRB genes.

Results: HLA and TR polymorphisms exerted broad effects on naive CD4+ TCR gene usage, with 38% of TRAV and 26% of TRBV genes being affected by HLA variants. Carriage of HLA-DQ2.5 was associated with increased usage of TCR genes implicated in stereotyped gluten epitope recognition, such as TRAV4, TRAV12-2 and TRBV5-1. TRA and TRB sequences known to recognize gluten peptides in the context of HLA-DQ2.5 were most frequent in CeD subjects and individuals carrying HLA-DQ2.5.

Conclusions: Our data demonstrate a clear HLA-effect on the naive CD4+ αβ TCR repertoire. HLA-DQ2.5 predisposes to CeD not only by promoting preferential binding and presentation of deamidated gluten peptides, but also by skewing the naive TCR repertoire toward T cells capable of recognizing such peptides. This supports a dual genetic mechanism of HLA-mediated CeD predisposition: selective peptide presentation and preconfiguration of a disease-relevant TCR repertoire.