A Critical Insulin TCR Contact Residue Selects High-Affinity and Pathogenic Insulin-Specific T Cells

Diabetes. 2020 Mar;69(3):392-400. doi: 10.2337/db19-0821. Epub 2019 Dec 13.

Abstract

Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Forkhead Transcription Factors / metabolism
  • Insulin / genetics
  • Insulin / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mutation
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Insulin
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • insulin B (9-23)