The MHC Reactivity of the T Cell Repertoire Prior to Positive and Negative Selection

T cell antigen receptors (TCRs) on mature T cells react with peptide antigens presented by self-MHC proteins and also frequently cross-react with foreign MHC proteins. The fundamental question whether MHC reactivity is inherent in the germline TCR sequences or is imposed by thymic selection was addressed here by inducing nonselective maturation of immature thymocytes in the absence of MHC molecules. MHC reactivity in the preselection repertoire is very high, but no higher than in the normal repertoire. Cross-reactivity of clones with multiple MHC molecules occurred to a similar extent in the preselection and MHC-selected repertoires. The results establish the MHC reactivity of the germline TCR repertoire, indicate the minimum fraction of immature thymocytes that must undergo negative selection, and suggest that some TCR-MHC contacts may be conserved.