T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes

Nat Commun. 2017 Nov 27;8(1):1792. doi: 10.1038/s41467-017-01925-2.

Abstract

Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2 × 108 TCRB sequences of circulating naive, central memory, regulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autoantigens / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Separation / methods
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology*
  • Complementarity Determining Regions / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Flow Cytometry / methods
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Thymus Gland / cytology
  • V(D)J Recombination / genetics
  • V(D)J Recombination / immunology*
  • Young Adult

Substances

  • Autoantigens
  • Complementarity Determining Regions
  • Receptors, Antigen, T-Cell, alpha-beta