Neuroantigen-specific CD8 T cells inhibit ongoing demyelinating disease by autoregulating CD4 T cell responses using temporally distinct IFNγ- and perforin-dependent mechanisms.

Abstract

Abstract Pathogenesis of immune-mediated demyelinating diseases like multiple sclerosis (MS) is thought to be governed by a complex cellular interplay between immunopathological and immunoregulatory responses. We have previously shown that neuroantigen-specific CD8 T cells have an unexpected protective role in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). In this study, we interrogated the immunotherapeutic potential of PLP178–191-specific CD8 T cells. Here, we show that PLP178–191-specific CD8 T cells, when administered post-disease onset, swiftly ameliorated EAE progression and suppressed PLP178–191-specific CD4 T cell responses as measured by delayed-type hypersensitivity (DTH). To accomplish DTH suppression, PLP178–191-specific CD8 T cells required differential production of perforin and IFNγ. Perforin was ancillary for the rapid suppressive action of PLP178–191-specific CD8 T cells, but was necessary for maintenance of optimal longer term DTH suppression. Conversely, IFNγ production by PLP178–191-specific CD8 T cells was necessary for swift DTH suppression, but was less significant for maintenance of longer term suppression. These data indicate that neuroantigen-specific CD8 T cells employ an ordered regulatory mechanism program over a number of days in vivo during demyelinating disease and have mechanistic implications for this immunotherapeutic approach.