MyD88, a central innate immune adaptor, is dispensable for spontaneous autoimmune demyelination in a mouse model of multiple sclerosis (P4077)

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune disease that is mediated by myelin-reactive T cells resulting in CNS demyelination. Mice that are transgenic for a myelin proteolipid protein (PLP)-specific T cell receptor (TCR) spontaneously develop experimental autoimmune encephalomyelitis (EAE), the animal model of MS. MyD88 is the key adaptor protein in Toll-like receptor (TLR), IL-1R and IL-18R signaling, resulting in the activation of innate immune cells, including DCs. Although, MyD88-signaling is critical for T cell responses against microbial agents, it is unknown whether it is required for priming of myelin-reactive T cells in spontaneous EAE or MS. Here, we investigated the requirement of MyD88-signaling for the pathogenesis of spontaneous EAE in PLP TCR transgenic mice that genetically lacked MyD88. We demonstrate that MyD88 is dispensable for the development of spontaneous EAE and autoimmune demyelination in these mice. MyD88-independent EAE was associated with activated DCs that showed superior ability to promote PLP-specific Th1 and Th17 responses in vitro compared to DCs from healthy counterparts. In addition, we provide evidence indicating that the MyD88-independent TRIF signaling pathway was induced in EAE-diseased mice. Taken together, our data suggest that MyD88-independent innate immune signaling critically contributes to priming of myelin-reactive T cells and initiation of spontaneous EAE in our MS model.