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Type I interferon (IFN-I) promotes antiviral CD8+T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8+T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8+T cell responses. In the absence of MDA5, CD8+T cell responses to acute infection rely on CD4+T cell help, and loss of both CD4+T cells and MDA5 results in CD8+T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8+T cells, promoting viral clearance. Thus, effective antiviral CD8+T cell responses depend on the timing and magnitude of IFN-I production.
► MDA5 is the key trigger of IFN-I that promotes CD8+T cell responses to LCMV ► In MDA5−/− mice infected with acute LCMV, CD8+T cells are sustained by CD4+T cells ► Chronic LCMV inhibits production of IFN-I, which facilitates CD8+T cell exhaustion ► Given early during chronic LCMV, IFN-I rescues CD8+T cells and clears the virus