TLR7 and CD28 regulate plasmacytoid dendritic cell IFN-I induction and silencing during chronic viral infection (INC8P.439)

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 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. Furthermore, gene expression profile comparisons of pDCs and conventional (c) DCs identified CD28, a prototypic T cell stimulatory receptor, as highly expressed in pDCs. Strikingly, CD28 acted in a cell-intrinsic manner to negatively regulate the magnitude of pDC IFN-I production upon TLR stimulation in vitro and early after in vivo LCMV infection, but was dispensable for the subsequent IFN-I silencing. In contrast, cell-intrinsic TLR7 signaling was essential for the later pDC IFN-I exhaustion observed in chronic LCMV infection and compromised innate responses against secondary opportunistic pathogens. These results highlight a novel role for CD28 in limiting the magnitude of pDC IFN-I production and a dual role for TLR7 in mediating both induction and subsequent exhaustion of innate responses during in vivo chronic viral infection.