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-Ed 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-Ed 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.
Cotton
J
J
Département d'Ingénierie et d'Etudes des Protéines, CEA-Saclay, Gif-sur-Yvette, France.
Hervé
M
M
Pouvelle
S
S
Maillère
B
B
Ménez
A
A
D000818:Animals; D004546:Elapid Venoms / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006825:Hybridomas; D008024:Ligands; D008213:Lymphocyte Activation; D008745:Methylation; D051379:Mice; D009498:Neurotoxins / Q000737:chemistry / Q000276:immunology; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
D004546:Elapid Venoms; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D008024:Ligands; D009498:Neurotoxins; D010455:Peptides