Anatomy of T cell autoimmunity to myelin oligodendrocyte glycoprotein (MOG): prime role of MOG44F in selection and control of MOG-reactive T cells in H-2b mice.
Myelin oligodendrocyte glycoprotein (MOG) is an important myelin target antigen, and MOG-induced EAE is now a widely used model for multiple sclerosis. Clonal dissection revealed that MOG-induced EAE in H-2(b) mice is associated with activation of an unexpectedly large number of T cell clones reactive against the encephalitogenic epitope MOG35-55. These clones expressed extremely diverse TCR with no obvious CDR3alpha/CDR3beta motif(s). Despite extensive TCR diversity, the cells required MOG40-48 as their common core epitope and shared MOG44F as their major TCR contact. Fine epitope-specificity analysis with progressively truncated peptides suggested that the extensive TCR heterogeneity is mostly related to differential recognition of multiple overlapping epitopes nested within MOG37-52, each comprised of a MOG40-48 core flanked at the N- and/or the C-terminus by a variable number of residues important for interaction with different TCR. Abrogation of both the encephalitogenic potential of MOG and T cell reactivity against MOG by a single mutation (MOG44F/MOG44A), together with effective down-regulation of MOG-induced EAE by MOG37-44A-52, confirmed in vivo the primary role for MOG44F in the selection/activation of MOG-reactive T cells. We suggest that such a highly focused T cell autoreactivity could be a selective force that offsets the extensive TCR diversity to facilitate a more "centralized control" of pathogenic MOG-related T cell autoimmunity.
Ben-Nun
Avraham
A
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel. avraham.ben-nun@weizmann.ac.il
Kerlero de Rosbo
Nicole
N
Kaushansky
Nathali
N
Eisenstein
Miriam
M
Cohen
Lydia
L
Kaye
Joel F
JF
Mendel
Itzhack
I
D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D018604:Epitope Mapping / Q000379:methods; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell