Molecular profile of the T cell receptors of regulatory and effector CD4+ T cells recognizing overlapping determinants on glutamic acid decarboxylase (524-543)

Jin S. Im, Anthony Quinn, Eli E. Sercarz, Douglas F. Lake

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Glutamic acid decarboxylase (GAD65) is one of the autoantigens that initiates pathogenic T cell responses against insulin-secreting pancreatic beta cells in Type 1 diabetes (T1D). Previously it was shown that spontaneously arising pathogenic T cell responses in the NOD mouse model are confined to GAD530-543 (p530). However, regulatory T cell subpopulations, which can prevent diabetes, can also be generated, for example, by immunization with GAD524-538 (p524) or GAD524-543. Interestingly, two functionally distinct subpopulations of T cells which recognize overlapping determinants of GAD524-543, p524 and p530, utilize distinct TCR Vβ families, Vβ4 for pathogenic, and Vβ12 for regulatory T cells. We characterized T cell receptors (TCRs) from each subpopulation of T cells and visualized p524-specific TCR/p524/I-Ag7 and p530-specific TCR/p530/I-Ag7 complexes via molecular modeling to help us understand, at a molecular level, the in vivo expansion of p524- or p530-specific T cells in the NOD model of T1D. The absolute restriction in Vβ usage but not Vα usage and conserved CDR3β lengths for both T cell subpopulations demonstrates that the beta chains are main contributors in shaping both p524/I-Ag7 and p530/I-Ag7 restricted TCRs. However, only Vβ4+ T cells but not Vβ12+ T cells contain a common motif (DWG) in CDR3β and may involve all of CDR1β, CDR2β, and CDR3β in the recognition of the C-terminus of p530. These observations imply that the spontaneously arising p530-restricted TCRs may be selected under stringent structural frameworks to bind p530/I-Ag7 with high affinity. Thus, the pathogenic p530-specific T cells may arise from a small pool of autoreactive T cells upon breaking tolerance.

Original languageEnglish (US)
Pages (from-to)971-980
Number of pages10
JournalMolecular Immunology
Volume40
Issue number13
DOIs
StatePublished - Feb 2004
Externally publishedYes

Keywords

  • Glutamic acid decarboxylase
  • T cell receptors
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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