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

Abstract

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 MBP111–119 and MBP87–95 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-α and IFN-γ 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/MBP111–119) 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.

Interferon‐β therapy reduces CD4+ and CD8+ T‐cell reactivity in multiple sclerosis

“…16 Also, CD8 + T-cell lines isolated from MS patients that recognized endogenously processed MBP belonged to the CD45RA -CD45RO + CD8 + memory T-cell subset. 34 Most recently, Okuda et al reported that activation of CD45RO + CD4 + memory T cells is associated with an exacerbation of MS, while activation of CD45RO + CD8 + memory T cells may reflect systemic immunological dysregulation in MS patients. 38 In our study, the degree of CD4 + and CD8 + T-cell proliferation correlated with the initial frequency of CD45RO + T cells in MS patients but not in healthy subjects (Fig.…”

“…[32][33][34] Crawford et al found that both CD4 + and CD8 + T cells recognizing CNS autoantigens are widely prevalent in MS patients and healthy individuals. 21 In our own study, the reactivity of both CD4 + and CD8 + T cells to MOG was considerably elevated in untreated MS patients compared to those in healthy donors; conventional [ 3 H]thymidine incorporation assays conducted in parallel with the CFSE assays resulted in the same significant differences between the groups (Fig.…”

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…In blood, even though myelin-specific CD8 T cells lines could be derived from MS patients as well as healthy controls [38][39][40][41], a higher frequency of CD8 T cells recognizing myelin proteins has been reported in MS patients [41,42]. These data are however controversial [43].…”

“…The adoptive transfer of H-2D b -restricted CD8 T cells specific for the short MOG 37-46 peptide also induces EAE into C57Bl/6 recipients [58]. Therefore, MOG is thought to contain at least 2 nested encephalitogenic epitopes: MOG [40][41][42][43][44][45][46][47][48] that elicits a CD4 T cell response in the context of H-2I-A b [59], and MOG [37][38][39][40][41][42][43][44][45][46] inducing a CD8 T cell response restricted to H-2D b [58]. Most recently, MOG 42-50 was found to bind to H-2D b molecule to elicit a CD8 T cell responses in MOG-deficient animals.…”

Chronological Changes of CD4+ and CD8+ T Cell Subsets in the Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis

“…However, myelin antigen specifi c CD8 + T cells are also seen in EAE mice and patients with MS (Biddison et al 1998;Huesby et al 2001;Sun et al 2001;Zang et al 2004;Crawford et al 2004;Ford and Evavold 2005). Adoptive transfer of MBP or MOG specifi c CD8 + T cells induces EAE in recipient mice (Huesby et al 2001;Ford and Evavold 2005), and CD8 + T cells isolated from MS patients specifi cally damage COS cells expressing MBP ex vivo (Zang et al 2004). Therefore, CD8 + T cells may play a predominant role in the development of MS or EAE than previously expected.…”