Pseudopeptide ligands for MHC II-restricted T cells

The potential therapeutic use of peptides to activate or anergize specific T cells is seriously limited by their susceptibility to proteolytic degradation, Classically, peptides are stabilized by incorporation of non-natural modifications including main chain modifications, In the case of MHC Ii-restricted peptides, the peptide backbone actively participates to the interaction with the MHC molecule and hence may preclude the peptidomimetic approach, We thus investigated whether a single amide bond modification influenced the peptide capacity to bind to a MHC II molecule and to stimulate specific T cells, Twenty pseudopeptide analogs of the I-E-d binder 24-36 peptide, whose sequence was derived from a snake neurotoxin, were obtained by replacing each amide bond of the peptide central part, by either a reduced psi[CH2-NH] or N-methylated psi[CO-NMe] peptide bond, In agreement with the major interacting role played by the peptide backbone, several peptides displayed a low, if any, capacity to bind to the MHC II molecule and did not lead to T cell stimulation, However, one-third of the peptides were almost as active as the 24-36 peptide in I-E-d binding assays and one-fifth in T cell stimulation assays, Among them, two pseudopeptides displayed native-like activity, Good binders were not necessarily good at stimulating T cells, demonstrating that main chain modification also affected T cell recognition, We thus showed that a peptidomimetic approach could create a new type of MHC II ligand to control T cell responses.