Immune-based self-recognition and failure to modulate this response are believed to contribute to the debilitating autoimmune pathology observed in multiple sclerosis (MS). Studies from its murine model, experimental autoimmune encephalomyelitis (EAE), have shown that neuroantigen-specific CD4+ T cells are capable of inducing disease, while their immune sibling, the CD8+ T cells, have largely been ignored. To understand their role in autoimmune demyelination, we first confirmed that, similar to our observations in human MS, there is robust induction of neuroantigen-reactive CD8+ T cells in several models, including MOG 35-55 /CFA-induced EAE. However, MOG 35-55 -specific CD8+ T-cells, when purified, were unable to adoptively transfer disease into naïve mice (in contrast to CD4+ T-cells). In fact, we observed that the transfer of these neuroantigen-specific CD8+ T cells was able to suppress the induction of EAE and to inhibit ongoing EAE. These regulatory CD8+ T cells produced IFN-γ and perforin and were able to kill MOG loaded CD4+ T-cells as well as CD4-depleted APC, suggesting a cytotoxic/suppressor mechanism. Inhibition of EAE was associated with both the modulation of APC function as well as decreased MOG-specific CD4+ T cell responses. Our studies reveal a novel and unexpected immune regulatory function for neuroantigen-specific CD8+ T cells and have interesting biologic and therapeutic implications.

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Murine experimental autoimmune encephalomyelitis (EAE) is an induced, autoimmune, demyelinating disease model for human multiple sclerosis (MS). Copaxone is an approved immunomodulatory therapy for MS that was discovered through studies in EAE. It is thought that the main mode of action of Copaxone is the induction of a Th1 to Th2 shift in CD4+ T-cells. We have shown that, in human MS, Copaxone therapy induces an upregulation of cytotoxic, suppressor CD8+ T-cell responses, suggesting that these cells are integrally involved in mediating the immune effects of this drug. In this study, we show that Copaxone induces robust CD8+ T-cell responses even in mice. Whereas Copaxone immunization ameliorates the clinical and histologic severity of EAE in wild type C57/BL6 mice, such protection is not observed in CD8(−/−) mice. Moreover, adoptive transfer of CD8+ T-cells from Copaxone-immunized (but not OVA-immunized) mice results in amelioration of EAE in CD8(−/−) mice, suggesting therapeutic potential for Copaxone-specific CD8+ T-cells. In conclusion, our studies provide strong evidence for the in vivo relevance of CD8+ T-cell responses during Copaxone therapy and support the hypothesis that the induction of immune modulatory CD8+ T-cells is an essential step in mediating therapeutic protection during autoimmune demyelination. This research was supported, in part, by grants from the National Institutes of Health and the National MS Society.

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