Specific T-cell receptor beta-rearrangements of gluten-triggered CD8+ T-cells are enriched in celiac disease patients' duodenal mucosa

Abstract

Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4⁺ T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8⁺ α/β intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRβ-rearrangements derived from gluten-specific CD4⁺ T-cells and gluten-triggered peripheral blood CD8⁺ T-cells. We show, that in addition to TCRs from gluten-specific CD4⁺ T-cells, TCRs of gluten-triggered CD8⁺ T-cells are significantly enriched in CeD duodenal tissue samples. TCRβ-rearrangements of gluten-triggered CD8⁺ T-cells were even more expanded in patients than TCRs from gluten-specific CD4⁺ T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens.

Keywords: Celiac disease; Influenza A; Refractory celiac disease; Somatic recombination; T-cell receptor.