A partially modified retro-inverso pseudopeptide modulates the cytokine profile of CTL specific for an influenza virus epitope.
There is considerable evidence that peptides corresponding to MHC class I-restricted epitopes can be used as immunogens or immunomodulators. Pseudopeptides containing isosteric replacements of the amide bond provide more stable analogues, which may even have enhanced biologic activity. But there have been very few studies on the use of pseudopeptides to initiate or modulate the cellular immune response. This study describes the immunogenicity of a partially modified retro-inverso pseudopeptide of an influenza virus epitope and shows that this pseudopeptide modulates the cytokine profile expressed by CD8+ CTL generated from primed precursors. Moreover, the pseudopeptide is much more efficient at low concentration than the wild-type epitope to stimulate IFN-gamma secretion by CD8+ T effector cells. These results are analyzed with reference to changes in the conformation of the MHC molecule/peptide complex deduced from molecular modeling. The findings support the idea that partially modified retro-inverso analogues can be used as altered peptide ligands to enhance the stimulation of natural epitope-specific CTL and to modify their functional properties. Hence, pseudopeptide ligands might be promising tools for use in immunotherapy.
Ostankovitch
M
M
Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, Institut National de la Santé et de la Recherche Médicale, U445, Université René Descartes, Paris, France. ostankovitch@cochin.inserm.fr
Guichard
G
G
Connan
F
F
Muller
S
S
Chaboissier
A
A
Hoebeke
J
J
Choppin
J
J
Briand
J P
JP
Guillet
J G
JG
D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000494:pharmacology; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D012333:RNA, Messenger; D014763:Viral Matrix Proteins; C098952:influenza virus membrane protein (58-66); D007371:Interferon-gamma