Germline-encoded amino acids in the alphabeta T-cell receptor control thymic selection

Nature. 2009 Apr 23;458(7241):1043-6. doi: 10.1038/nature07812. Epub 2009 Mar 4.

Abstract

An alphabeta T-cell response depends on the recognition of antigen plus major histocompatibility complex (MHC) proteins by its antigen receptor (TCR). The ability of peripheral alphabeta T cells to recognize MHC is at least partly determined by MHC-dependent thymic selection, by which an immature T cell survives only if its TCR can recognize self MHC. This process may allow MHC-reactive TCRs to be selected from a repertoire with completely random and unbiased specificities. However, analysis of thymocytes before positive selection indicated that TCR proteins might have a predetermined ability to bind MHC. Here we show that specific germline-encoded amino acids in the TCR promote 'generic' MHC recognition and control thymic selection. In mice expressing single, rearranged TCR beta-chains, individual mutation of amino acids in the complementarity-determining region (CDR) 2beta to Ala reduced development of the entire TCR repertoire. Altogether, these results show that thymic selection is controlled by germline-encoded MHC contact points in the alphabeta TCR and indicate that the diversity of the peripheral T-cell repertoire is enhanced by this 'built-in' specificity.

Publication types

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

MeSH terms

  • Amino Acids / genetics*
  • Amino Acids / metabolism*
  • Animals
  • Bone Marrow / immunology
  • Bone Marrow / metabolism
  • Cell Line
  • Chimera / immunology
  • Chimera / metabolism
  • Complementarity Determining Regions / chemistry
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Germ Cells / metabolism*
  • Hybridomas / immunology
  • Major Histocompatibility Complex / immunology
  • Mice
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry*
  • Receptors, Antigen, T-Cell, alpha-beta / deficiency
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Thymus Gland / cytology*
  • Thymus Gland / immunology*

Substances

  • Amino Acids
  • Complementarity Determining Regions
  • Receptors, Antigen, T-Cell, alpha-beta