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

• Published in: The Journal of biological chemistry Vol. 276; no. 22; pp. 19396 - 19403
• Main Authors: Hudrisier, D, Riond, J, Burlet-Schiltz, O, von Herrath, M G, Lewicki, H, Monsarrat, B, Oldstone, M B, Gairin, J E
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 01.06.2001
• Subjects: Adaptive immunology; Adoptive Transfer; Amino Acid Sequence; Animals; Antigens - metabolism; Autoimmune Diseases - etiology; Biochemistry, Molecular Biology; CD4 Antigens - metabolism; CD8-Positive T-Lymphocytes - metabolism; Cell Division; Cell Line; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Epitopes; Humans; Immunology; Inhibitory Concentration 50; Innate immunity; Insulin - genetics; Interferon-gamma - biosynthesis; Life Sciences; Major Histocompatibility Complex; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Mutation; Peptides - chemistry; Promoter Regions, Genetic; Protein Binding; Rats; Spleen - cytology; Spleen - metabolism; Structural Biology; Structure-Activity Relationship; Time Factors; Transplantation; ESI-MS; electrospray ionization mass spectrometry; IFN-γ; interferon
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M008864200

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.