Unexpected reactivities of T cells selected by a single MHC-peptide ligand

In H2-DM mutant mice, most MHC class II molecules are bound by a single peptide, CLIP, derived from the class II-associated invariant chain. Previous studies showed that H2-DM^- cells are defective in presenting synthetic peptides to class II-restricted T cells. In sharp contrast, however, the same peptides elicited strong CD4⁺ T cell responses in H2-DM^- animals. We now provide an explanation for this apparent discrepancy. Peptide-specific CD4⁺ T cells from wild-type mice were efficiently stimulated by H2-DM⁺, but not by H2-DM^- cells pulsed with the cognate peptide. In sharp contrast, CD4⁺ T cells from mutant animals specific for the same MHC-peptide combination recognized peptide-pulsed H2-DM⁺ and H2-DM^- cells equally well. In addition, unlike Ag-specific T cells from wild-type animals, the reactivities of peptide-specific T cells from mutant animals could not be efficiently blocked by Abs specific for the cognate MHC class H-peptide combination. We further demonstrated that the distinct reactivities of CD4⁺ T cells from H2- DM⁺ and H2-DM^- mice are due to differences in thymic selection. Collectively, these findings indicate that the CD4⁺ T cell repertoires of H2-DM⁺ and H2-DM^- mice are remarkably different.