TCRs with high affinity for foreign pMHC show self-reactivity

Nat Immunol. 2003 Jan;4(1):55-62. doi: 10.1038/ni863. Epub 2002 Dec 9.


T cells with high-affinity T cell receptors (TCRs) for a foreign peptide-major histocompatibility complex (pMHC) appear to be negatively selected, even though they have never seen the foreign antigen. To examine how this process operates, we used in vitro yeast display to isolate high-affinity TCRs from the T cell clone 2C. The TCRs showed fast on-rates, which were consistent with reduced CDR (complementarity determining region) flexibility, and cross-reactivity with other cognate pMHCs. T cell hybridomas transfected with a high-affinity TCR were stimulated by endogenous self-pMHC, which suggested that T cells bearing the TCR would be negatively selected. The immune system appears to maintain a repertoire of flexible, low-affinity TCRs at the expense of more effective high-affinity TCRs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoantigens
  • Complementarity Determining Regions
  • Cross Reactions
  • Hybridomas / immunology
  • In Vitro Techniques
  • Kinetics
  • Macromolecular Substances
  • Major Histocompatibility Complex*
  • Mice
  • Models, Molecular
  • Peptide Library
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology
  • Thermodynamics


  • Autoantigens
  • Complementarity Determining Regions
  • Macromolecular Substances
  • Peptide Library
  • Receptors, Antigen, T-Cell