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

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Abstract
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-2b 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 CDR3α/CDR3β 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.

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