Timing and magnitude of type i interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection

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.