Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: Diverse VP gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V beta(b) and T cell receptor V beta(a) H-2(b) mice

The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig-like domain of human MOG is associated, in H-2(b) mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35-55, accounting for the previously reported strong encephalitogenic activity of pMOG 35-55. A single injection of pMOG 35-55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H-2(b) mice. Encephalitogenic pMOG 35-55-specific T cell lines derived from C3H.SW (V beta(b)) mice were diverse in their TCR V beta gene usage (V beta 1, V beta 6, V beta 8 and V beta 15), although V beta 8.2 was most predominantly expressed (48%). However, V beta 8(+) T cells may only be part of the encephalitogenic MOG-specific T cell repertoire in H-2(b) mice, as demonstrated by the susceptibility of C57L (V beta(a)) mice to disease induced by pMOG 35-55. Encephalitogenic T cell lines from V beta(a) mice were also diverse in their TCR V beta gene usage (V beta 1, V beta 2, V beta 6, V beta 14 and V beta 16). Such a heterogeneous TCR V beta gene expression by pMOG 35-55/I-A(b)-reactive T cells from both V beta(a) and V beta(b) H-2(b) mice suggested multiple epitopes within pMOG 35-55. Analysis of the pattern of reactivity by pMOG 35-55-reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement fur recognition of a core sequence, YRSPFSRVV (pMOG 40-48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid Ranking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40-48 Nonetheless, pMOG 40-48 was the minimal encephalitogenic epitope for both V beta(a) and V beta(b) mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse V beta gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope-directed, rather than TCR-targeted, approaches to immunospecific therapy for MOG-related autoimmune disease.