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Toso controls encephalitogenic immune responses by dendritic cells and regulatory T cells

Significance More than 1 million people worldwide suffer from the debilitating neurological disorder multiple sclerosis (MS). The initiation of MS is associated with sustained inflammation and an autoimmune T-cell response targeting the central nervous system. The activities of Th1 and Th17 effector T cells, which are the main pathogenic drivers of MS, are balanced by regulatory T cells, which dampen inflammation and mitigate disease. Our study describes an important role for the surface receptor Toso in balancing these T-cell subsets and controlling inflammation. Using an animal model of MS, we have developed a preclinical treatment strategy in which Toso-Fc fusion protein ameliorates the inflammatory symptoms of experimental autoimmune encephalomyelitis, an MS-like disease. The ability to mount a strong immune response against pathogens is crucial for mammalian survival. However, excessive and uncontrolled immune reactions can lead to autoimmunity. Unraveling how the reactive versus tolerogenic state is controlled might point toward novel therapeutic strategies to treat autoimmune diseases. The surface receptor Toso/Faim3 has been linked to apoptosis, IgM binding, and innate immune responses. In this study, we used Toso-deficient mice to investigate the importance of Toso in tolerance and autoimmunity. We found that Toso−/− mice do not develop severe experimental autoimmune encephalomyelitis (EAE), a mouse model for the human disease multiple sclerosis. Toso−/− dendritic cells were less sensitive to Toll-like receptor stimulation and induced significantly lower levels of disease-associated inflammatory T-cell responses. Consistent with this observation, the transfer of Toso−/− dendritic cells did not induce autoimmune diabetes, indicating their tolerogenic potential. In Toso−/− mice subjected to EAE induction, we found increased numbers of regulatory T cells and decreased encephalitogenic cellular infiltrates in the brain. Finally, inhibition of Toso activity in vivo at either an early or late stage of EAE induction prevented further disease progression. Taken together, our data identify Toso as a unique regulator of inflammatory autoimmune responses and an attractive target for therapeutic intervention.