Structural and functional identification of major histocompatibility complex class I-restricted self-peptides as naturally occurring molecular mimics of viral antigens. Possible role in CD8+ T cell-mediated, virus-induced autoimmune disease.
Structural similarity (molecular mimicry) between viral epitopes and self-peptides can lead to the induction of autoaggressive CD4(+) as well as CD8(+) T cell responses. Based on the flexibility of T cell receptor/antigen/major histocompatibility complex recognition, it has been proposed that a self-peptide could replace a viral epitope for T cell recognition and therefore participate in pathophysiological processes in which T cells are involved. To address this issue, we used, as a molecular model of viral antigen, the H-2D(b)-restricted immunodominant epitope nucleoprotein (NP)-(396-404) (FQPQNGQFI) of lymphocytic choriomeningitis virus (LCMV). We identified peptide sequences from murine self-proteins that share structural and functional homology with LCMV NP-(396-404) and that bound to H-2D(b) with high affinity. One of these self-peptides, derived from tumor necrosis factor receptor I (FGPSNWHFM, amino acids 302-310), maintained LCMV-specific CD8(+) T cells in an active state as observed both in vitro in cytotoxic assays and in vivo in a model of virus-induced autoimmune diabetes, the rat insulin promoter-LCMV NP transgenic mouse. The natural occurrence and molecular concentration at the surface of H-2(b) spleen cells of tumor necrosis factor receptor I-(302-310) were determined by on-line micro-high pressure liquid chromatography/mass spectrometry and supported its biological relevance.
Institut de Pharmacologie et de Biologie Structurale, CNRS, 205 route de Narbonne, 31400 Toulouse, France.
D
D
Hudrisier
J
J
Riond
O
O
Burlet-Schiltz
M G
MG
von Herrath
H
H
Lewicki
B
B
Monsarrat
M B
MB
Oldstone
J E
JE
Gairin
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D008285:Major Histocompatibility Complex; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014180:Transplantation
D000941:Antigens; D015704:CD4 Antigens; D000939:Epitopes; D007328:Insulin; D010455:Peptides; D007371:Interferon-gamma