The lifespan of major histocompatibility complex class I peptide complexesdetermines the efficiency of cytotoxic T-lymphocyte responses

Major histocompatibility complex (MHC)/peptide association and stability ar e determined by specific amino acid interactions between peptide antigens a nd the MHC groove, and are regarded as a critical feature in ensuring effic ient monitoring by T cells. In this investigation we examined the relations hip between MHC/peptide stability and the immunostimulatory capacity of MHC / peptide complexes. For this purpose we compared synthetic peptide analogu es derived from the immunodominant HLA-A11-presented IVTDFSVIK (IVT) epitop e, for their capacity to reactivate IVT-specific memory cytotoxic T-lymphoc yte (CTL) responses. The analogues differentiated from the wild-type epitop e by single amino acid substitution at position 2. All peptides showed simi lar affinity for HLA-A11 molecules and were recognized by IVT-specific CTL clones, but induced HLA-A11 complexes at the cell surface with different li fespan. This model offered the possibility of comparing the capacity of an immunogenic epitope to stimulate a unique population of T-cell precursors d epending on the lifespan of its presentation at the cell surface. We demons trated that stable HLA-A11/peptide complexes efficiently stimulate IVT-spec ific CTL responses, while HLA-A11/peptide complexes with short lifespan do not. The precise identification of the role of amino acid residues in the f ormation of stable MHC/peptide complexes may be relevant for the design of wild-type-derived epitopes with high immunogenicity. These analogues may ha ve important applications in the immunotherapy of infectious diseases and i mmunogenic tumours.