Selection of Antigen-specific T Cells by a Single IE^k Peptide Combination

In normal mice, major histocompatibility complex (MHC) proteins are bound to many different peptides, derived from the proteins of their host. In the thymus, the diversity of this collection of MHC + peptide ligands allows thymocytes bearing many different T cell receptors (TCRs) to mature by low avidity reactions between the MHC + peptide ligands and the thymocyte TCRs. To investigate this problem, the selection of T cells specific for a well-studied combination of MHC + peptide, IE^k + moth cytochrome c 88–103 (MCC), was investigated. Mice were created that expressed IE^k bound to a single peptide, either a variant of MCC in which a critical TCR contact residue, 99K, was changed to A, or a variant of a mouse hemoglobin 64–76 (Hb) peptide, 72A. IE^k bound to the MCC variant caused the clonal deletion of some T cells specific for the IE^k + MCC ligand; nevertheless, it also positively selected many T cells that could react with this ligand. Some of the TCRs on the selected T cells were related to those on cells from normal mice and some were not. IE^k bound to the Hb variant, on the other hand, did not select any T cells which could react with IE^k + MCC. These results demonstrate that although positive selection is a partially degenerate event, the sequence of the peptide involved in positive selection controls the selected repertoire.