Subtle changes in TCRα CDR1 profoundly increase the sensitivity of CD4 T cells

Jennifer N. Lynch, David L. Donermeyer, K. Scott Weber, David M. Kranz, Paul M. Allen

Research output: Contribution to journalArticle

Abstract

Changes in the peptide and MHC molecules have been extensively examined for how they alter T cell activation, but many fewer studies have examined the TCR. Structural studies of how TCR differences alter T cell specificity have focused on broad variation in the CDR3 loops. However, changes in the CDR1 and 2 loops can also alter TCR recognition of pMHC. In this study we focus on two mutations in the CDR1α loop of the TCR that increased the affinity of a TCR for agonist Hb(64-76)/I-Ek by increasing the on-rate of the reaction. These same mutations also conferred broader recognition of altered peptide ligands. TCR transgenic mice expressing the CDR1α mutations had altered thymic selection, as most of the T cells were negatively selected compared to T cells expressing the wildtype TCR. The few T cells that escaped negative selection and were found in the periphery were rendered anergic, thereby avoiding autoimmunity. T cells with the CDR1α mutations were completely deleted in the presence of Hb(64-76) as an endogenous peptide. Interestingly, the wildtype T cells were not eliminated, identifying a threshold affinity for negative selection where a 3-fold increase in affinity is the difference between incomplete and complete deletion. Overall, these studies highlight how small changes in the TCR can increase the affinity of TCR:pMHC but with the consequences of skewing selection and producing an unresponsive T cell.

Original languageEnglish (US)
Pages (from-to)283-294
Number of pages12
JournalMolecular Immunology
Volume53
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Affinity
  • Anergy
  • CD4
  • CDR1
  • Selection
  • T cell

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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