TLR7 is required for both plasmacytoid dendritic cell IFN-I production and subsequent exhaustion during chronic viral infection (INC6P.309)

Abstract Type I Interferons (IFN-I) are potent cytokines essential for immune surveillance against many pathogens including persistent viruses such as human immunodeficiency virus (HIV) in humans and Lymphocytic Choriomeningitis Virus (LCMV) in mice. Plasmacytoid dendritic cells (pDCs) are specialized to produce IFN-I upon TLR stimulation, but the molecular mechanisms underlying their initial IFN-I production and the subsequent exhaustion that occurs during chronic viral infection remain to be fully elucidated. Using chronic LCMV infection in mice, we demonstrated that pDCs initially sensed and produced abundant IFN-I in a TLR7-dependent manner. Strikingly, cell-intrinsic TLR7 signaling was also essential for the later pDC IFN-I exhaustion observed in chronic LCMV infection and compromised innate responses against secondary opportunistic pathogens. Interestingly, when analyzing pDC bone marrow progenitors, we found that they were reduced in LCMV chronically infected mice, they had compromised developmental potential and only generated exhausted pDCs. Overall, our studies highlight a dual role for TLR7 in contributing to both induction and subsequent exhaustion of innate responses and suggest a pDC progenitor defect underlying IFN-I exhaustion during chronic viral infection.