A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

T-Cell Properties Determine Disease Site, Clinical Presentation, and Cellular Pathology of Experimental Autoimmune Encephalomyelitis

“…24 -27,37,38 Greer and colleagues, 38 Muller and colleagues, 24 26 describe an atypical or nonclassical clinical presentation of EAE induced in recipients of T H 2 cells producing high levels of IL-5, derived from B10.PL mice transgenically expressing a TCR for MBP Ac1-11; the description of spinning and rolling is very similar to axial-rotatory EAE described by Greer and colleagues, 38 Muller and colleagues, 24 and Sobel, 25 and observed here. Finally, Huseby and colleagues 27 describe a similar clinical presentation of EAE induced in C3H recipients of class I-restricted MBP 79-87-recognizing CD8 ϩ T cells from C3H/HeJ mice.…”

Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

“…Adoptive transfer of MOG-reactive CD8 + T cells into naive syngeneic recipient mice (Sun et al, 2001;Ford and Evavold, 2005), or adoptive transfer of T cell lines derived from MBP knockout mice infected with a recombinant vaccinia virus expressing MBP (Huseby et al, 2001), can evoke a clinical syndrome reminiscent of EAE with inflammatory neuropathology that is distinct from CD4 + T cell mediated disease models (Huseby et al, 2001;Ji and Goverman, 2007). However, in some cases EAE is observed only if the recipient mice have been irradiated prior to cell transfer.…”

“…These data indirectly implicated CD8 + T cells in EAE pathogenesis, and more recent reports have shown clearly that CD8 + T cells can trigger disease. When adoptively transferred into naive mice, myelin-reactive CD8 + T cells taken from mice immunized with certain myelin oligodendrocyte glycoprotein (MOG) peptides have the capacity to induce EAE (Huseby et al, 2001;Sun et al, 2001;Sun et al, 2003;Ford and Evavold, 2005;Ford and Evavold, 2006). How might CD8 + T cells be involved in EAE pathogenesis?…”

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

“…It was not known until recently that CD8 ϩ T cells recognizing short peptides of MBP can induce EAE with distinct CNS pathology. These CD8 ϩ T cells are cytotoxic toward target cells in the recognition of endogenously processed MBP and induced severe EAE upon adoptive transfer (4,5). It is important to note that CNS lesions induced by CD8 ϩ CTLs recognizing MBP are characterized by extensive demyelination, closely resembling MS pathology in humans (4), suggesting that CD8 ϩ CTLs recognizing MBP are capable of causing injury of oligodendrocytes expressing both MHC class I molecules and MBP.…”