Mutations in the major histocompatibility complex class I antigen-presenting groove affect both negative and positive selection of T cells

Abstract

In several transgenic mouse models T cell development was shown to be controlled by the binding of the alpha/beta T cell receptor (TcR) to ligands in the thymus. In transgenic mice expressing a male-specific TcR alpha/beta, the presence of the restricting D major histocompatibility complex (MHC) molecule plus the male specific peptide deleted thymocytes at an early stage of development. On the other hand, maturation of T cells required an interaction of the TcR with the thymic D MHC molecules in the absence of specific peptides. This could imply that negative and positive selection of this receptor are affected differently by mutations in the HY peptide-binding groove of the D MHC molecule. Such mutants have been isolated and were shown to affect the response to HY antigen in that both the bm14 (residue Glu70----Asp) and the bm13 (residue Leu114----Glu, Phe116----Tyr and Glu119----Asp) strains do not normally mount cytotoxic responses to male cells. Here we show that these mutations affect antigenicity of male cells, as well as negative and positive selection of T cells in TcR alpha/beta transgenic mice.