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

Mucosal Immunol. 2016 May;9(3):587-96. doi: 10.1038/mi.2015.147. Epub 2016 Feb 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • Celiac Disease / immunology*
  • Cell Differentiation
  • Cells, Cultured
  • Clonal Selection, Antigen-Mediated
  • DNA / analysis*
  • Glutens / immunology
  • HLA-DQ Antigens / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunodominant Epitopes / immunology
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell / genetics*
  • Single-Cell Analysis

Substances

  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • Immunodominant Epitopes
  • Receptors, Antigen, T-Cell
  • Glutens
  • DNA