In the normal repertoire of CD4+ T cells, a single class II MHC/peptide complex positively selects TCRs with various antigen specificities

In the thymus, immature T cells are positively and negatively selected by multiple interactions between their Ag receptors (TCRs) and self MHC/peptide complexes expressed on thymic stromal cells. Here we show that in the milieu of negative selection on physiological self class II MHC/peptide complexes (Abwt), a single class II/peptide complex AbEp52-68 positively selects a number of TCRs with various Ag specificities. This TCR repertoire is semidiverse and not biased toward Ep-like Ags. Our finding implies that the degeneracy of positive selection for peptide ligands exceeds peptide-specific negative selection and is essential to increase the efficiency and diversity of the repertoire so that T cells with the same Ag specificity can be selected by different self MHC/ peptide complexes.