TCR sequencing of single cells reactive to DQ2.5-glia-α2 and DQ2.5-glia-ω2 reveals clonal expansion and epitope-specific V-gene usage

• Published in: Mucosal immunology 2016-05, Vol.9 (3), p.587-596
• Main Authors: Dahal-Koirala, S, Risnes, L F, Christophersen, A, Sarna, V K, Lundin, K EA, Sollid, L M, Qiao, S W
• Format: Article
• Language: English
• Subjects: 631/250/1619/554/1775; 631/250/347; 631/61/514; 692/699/2743/1313/1357; Allergology; Antibodies; Antigens; Antiretroviral drugs; Biomedicine; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Celiac disease; Celiac Disease - immunology; Cell Differentiation; Cells, Cultured; Clonal Selection, Antigen-Mediated; Disease; DNA - analysis; Epitopes; Gastroenterology; Gluten; Glutens - immunology; High-Throughput Nucleotide Sequencing; Histocompatibility antigen HLA; HLA-DQ Antigens - metabolism; Humans; Immunodominance; Immunodominant Epitopes - immunology; Immunology; Inflammatory diseases; Lymphocyte Activation; Lymphocytes T; Receptors, Antigen, T-Cell - genetics; Single-Cell Analysis; T cell receptors
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/mi.2015.147

CD4+ T cells recognizing dietary gluten epitopes in the context of disease-associated human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 molecules are the key players in celiac disease pathogenesis. Here, we conducted a large-scale single-cell paired T-cell receptor (TCR) sequencing study to characterize the TCR repertoire for two homologous immunodominant gluten epitopes, DQ2.5-glia-α2 and DQ2.5-glia-ω2, in blood of celiac disease patients after oral gluten challenge. Despite sequence similarity of the epitopes, the TCR repertoires are unique but shared several overall features. We demonstrate that clonally expanded T cells dominate the T-cell responses to both epitopes. Moreover, we find V-gene bias of TRAV26 , TRAV4 , and TRBV7 in DQ2.5-glia-α2 reactive TCRs, while DQ2.5-glia-ω2 TCRs displayed significant bias toward TRAV4 and TRBV4 . The knowledge that antigen-specific TCR repertoire in chronic inflammatory diseases tends to be dominated by a few expanded clones that use the same TCR V-gene segments across patients is important information for HLA-associated diseases where the antigen is unknown.