Listeria monocytogenes-encoded expression of a neuroantigen induces CD8 T-cell-mediated inhibition of autoimmune demyelinating disease

Abstract

Abstract CD8 T-cells predominate in the central nervous system (CNS) lesions of multiple sclerosis (MS), an autoimmune demyelinating disease, yet their function remains controversial. We have previously shown that myelin-specific CD8 T-cells suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Here, we describe a novel system to probe the role of endogenously generated myelin specific-CD8 T-cell responses in CNS autoimmunity. A sequence encoding proteolipid protein peptide PLP178-191 was inserted into attenuated Listeria monocytogenes (LM), deleted for the actA and inlB genes. PLP178-191-specific CD8 T-cell responses were confirmed by infecting B6 mice with the LM-PLP strain and assessing peptide-induced IFN-γ production. We tested the effect of LMP-PLP infection on chronic (B6 mice) and relapsing-remitting (SJL mice) forms of EAE. In both systems, infection with LM-PLP did not result in disease induction. In contrast, LM-PLP infection resulted in significant amelioration of clinical disease in PLP178-191-immunized B6 and SJL mice, compared to LM-OVA-infected controls. LM-PLP infection also effectively suppressed relapses in SJL/J mice. Interestingly, LM-PLP-induced protection was not observed in CD8(−/−) B6 mice, indicating the importance of CD8 T-cells in mediating this effect. Our studies indicate that myelin-specific CD8 T-cell responses generated following LM-PLP175-194 infection are not encephalitogenic and attenuate CNS autoimmunity in multiple mouse models of EAE, further strengthening their role as regulators of disease and their potential as a novel immunotherapeutic strategy.