Fine chemical modifications at N- and C-termini enhance peptide presentation to T cells by increasing the lifespan of both free and MHC-complexed peptides.
We investigated the effect of modifying the N- and/or C-termini of the snake toxin peptide 24-36 on its presentation to T cells. Acetylation at the N-terminus as well as amidation at the C-terminus enhanced the capacity of the peptide to activate T cells. Simultaneous modifications further increased the stimulating activity, the peptide becoming approximately 100-fold more potent than the unmodified peptide. Clearly, the introduced modifications increased the lifetime of the peptide free in solution, by decreasing its proteolytic degradation, during the T cell stimulation assays. Paradoxically, however, at similar concentrations of free peptides, the modified ones, especially those having an acetylated N-terminus, were much more active than the unmodified peptide, irrespective of the experimental conditions. These observations suggested that components other than protection from proteolytic degradation should be associated with the higher stimulating activities of the modified peptides. Accordingly, chasing experiments with APC revealed that acetylation at N-terminus caused a higher persistence of the peptides at APC surface. Together, our data indicate that (i) the T cell stimulating capacity of a peptide is associated with its lifespans in the free and MHC II bound states; and (ii) these lifespans can be greatly enhanced by introducing fine chemical modifications at N- and C-termini. These data may have some implications in designing more potent peptidic immunomodulators.
Maillère
B
B
CEA, Département d'Ingénierie et d'Etudes des Protéines, Gif-sur-Yvette, France.
Mourier
G
G
Hervé
M
M
Ménez
A
A
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000737:chemistry; D000954:Antigens, Surface / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology*; D006825:Hybridomas; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology*
D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D046911:Macromolecular Substances; D010455:Peptides