International Immunology, Vol 10, 159-166, Copyright © 1998 by Oxford University Press
J Cotton, M Herve, S Pouvelle, B Maillere and A Menez
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.
ARTICLES
Pseudopeptide ligands for MHC II-restricted T cells
Departement d'Ingenierie et d'Etudes des Proteines, CEA-Saclay, Gif-sur- Yvette, France.
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