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J. Biol. Chem., Vol. 276, Issue 22, 19396-19403, June 1, 2001
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From the 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-2Db-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-2Db 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-2b spleen cells of tumor
necrosis factor receptor I-(302-310) were determined by on-line
µ-high pressure liquid chromatography/mass spectrometry and
supported its biological relevance.
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*
§¶,§,§,
,,,, and**
Institut de Pharmacologie et de Biologie
Structurale, CNRS, 205 route de Narbonne, 31400 Toulouse, France and
the Department of Neuropharmacology, Division of Virology,
Scripps Research Institute, La Jolla, California 92037
*
This work was supported in part by grants from CNRS;
Association pour la Recherche sur le Cancer Contract 5485, Région Midi-Pyrénées; National Institutes of
Health Grants AI41439, AI09484 (to M. B. A. O.), and AI44451 (to
M. G. v. H.); and a Juvenile Diabetes International
Foundation career development award (to M. G. v. H.). This is
Publication 13360-NP from the Department of Neuropharmacology, Scripps
Research Institute (La Jolla, CA).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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