In vivo positive selection determines the peptide and MHC specificity of the CD8 T cell repertoire

Abstract

The nature of the peptides that drive positive selection of T cells in the thymus remains poorly defined. To examine the role of peptides during positive selection in vivo, we generated single‐chain‐trimer (SCT) transgenic mouse strains that express only the OVAp/Kb/β2m complex or the VSVp/Kb/β2m complex. Although the SCT transgene is expressed at levels that are comparable to Kb expression in B6 mice, very few CD8 T cells are selected by the SCT compared to B6 mice, a finding consistent with positive selection being peptide specific. Furthermore, the SCT selected CD8 T cells are highly reactive with Kb loaded with endogenous peptides, but are not reactive with Db. This demonstrates that endogenous Kb self peptides are effectively excluded by the covalently attached peptide, and that CD8 T cells preferentially react with the selecting class I molecule. A T cell clonal analysis revealed that SCT selected T cells were highly specific for Kb and were not more MHC cross‐reactive than T cells from B6 mice. These results suggest that CD8 T cells selected on a single peptide/MHC ligand are MHC specific and possess at least some peptide cross‐reactivity. The extent of this peptide cross reactivity is under investigation to define the relationship between the selecting and agonist peptides. In sum, these data strongly suggest that positive selection determines the peptide and MHC specificity of the CD8 T cell repertoire.