Heteroclitic properties of mixed α- and aza-β 3-peptides mimicking a supradominant CD4 T cell epitope presented by nucleosome

• Published in: Molecular immunology Vol. 44; no. 11; pp. 3024 - 3036
• Main Authors: Dali, Hayet, Busnel, Olivier, Hoebeke, Johan, Bi, Lanrong, Decker, Patrice, Briand, Jean-Paul, Baudy-Floc’h, Michèle, Muller, Sylviane
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2007
• Subjects: Altered peptide ligand; Autoimmunity; Aza-b3 amino acids; Histones; MHC-Peptide interaction; Peptide analogues; Systemic lupus erythematosus; T cell epitope; Vaccination; Autoimmunity; Systemic lupus erythematosus; MHC-Peptide interaction; Aza-b3 amino acids; Vaccination; Histones; T cell epitope; Peptide analogues; Altered peptide ligand
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2006.12.028

Recent studies have revealed that peptide analogues containing modified peptide bonds might replace poorly stable natural peptides in therapeutic strategies. Using the model peptide 88–99 of histone H4, which contains a supradominant epitope recognized by Th cells induced to nucleosomes, we have generated twelve analogues containing aza-β 3-amino acid residue substitutions. The ability of this new class of peptidomimetics corresponding to the Ψ[CONHNRCH 2] modification to be recognized by T cells primed with the parent peptide was examined in BALB/c mice. An Ala-scan study revealed that residues 88 to 92 were essential for keeping antigenic activity of the nominal peptide. In good agreement, the six aza-β 3-analogues encompassing substitutions in the region 89–92 were antigenically inactive. Analogues ΨG94 and ΨG99 were both antigenic and immunogenic, though at levels that were slightly lower to that of the parent peptide. However, the remaining analogues ΨR95, ΨL97, ΨY98 and ΨL97–Y98 were strongly recognized by T cells generated to the homologous peptides. The ΨL97–Y98 analogue, in particular, strongly activated CD4 + T cells as visualized in CFSE dilution assay. T cells primed to these four analogues and recalled with the nominal peptide secreted high levels of either IL-2 (ΨR95, ΨY98) or IFN-γ (ΨL97, ΨL97–Y98). This result, supported by molecular modeling, suggests that TCRs of T cells primed to these four analogues recognized the parent peptide associated with the MHC I-A d/I-E d molecules. Since these T cells produce a distinct cytokine pattern when they are recalled with the parent sequence, this new class of analogues may have valuable applications in the context of self-tolerance and autoimmunity.