Central tolerance spares the private high-avidity CD4(+) T-cell repertoire specific for an islet antigen in NOD mice

Eur J Immunol. 2015 Jul;45(7):1946-56. doi: 10.1002/eji.201445290. Epub 2015 May 12.


Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear. Here, we analyzed the TCRαβ repertoire of CD4(+) T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαβ repertoire of S100β-specific CD4(+) T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate- to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4(+) T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4(+) T-cell repertoire; the latter is deleted by re-enforced negative selection.

Keywords: Autoimmunity; Avidity; CD4+ T cells; NOD; T-cell tolerance; TCR repertoire.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Central Tolerance / immunology*
  • Diabetes Mellitus, Type 1 / immunology
  • Flow Cytometry
  • Islets of Langerhans / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • S100 Calcium Binding Protein beta Subunit / immunology*
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / immunology


  • Receptors, Antigen, T-Cell, alpha-beta
  • S100 Calcium Binding Protein beta Subunit
  • S100b protein, mouse
  • Serine Endopeptidases