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Increased CD8⁺ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis¹

Ying C. Q. Zang^2,*, Sufang Li^*, Victor M. Rivera^*, Jian Hong^*, Rachel R. Robinson^*, Wini T. Breitbach^*, James Killian^* and Jingwu Z. Zhang^*,,

^* Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, and Department of Immunology, Baylor College of Medicine, Houston, TX 77030; and Health Science Center, Shanghai Institutes of Biological Sciences and Shanghai Second Medical University, Immunology E-Institute of Shanghai Universities, Shanghai, People’s Republic of China

Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8⁺ T cell responses and their functional properties in patients with MS. There were significantly increased CD8⁺ T cell responses to 9-mer MBP peptides, in particular MBP_111–119 and MBP_87–95 peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8⁺ T cell lines were of the Th1 phenotype, producing TNF- and IFN- and belonged to a CD45RA⁻/CD45RO⁺ memory T cell subset. Further characterization indicated that the CD8⁺ T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP_111–119) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8⁺ T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8⁺ CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.

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