UC San Diego

Dendritic cells play a critical role in orchestrating a robust immune response against viral infections. These specialized cells are responsible for various functions including, the production of type I interferon, (IFN-I) which plays a critical role in both innate and adaptive immune responses against viral infections. Chronic viral infections such as HIV and HCV in humans, and lymphocytic choriomeningitis virus (LCMV) in mice, lead to dendritic cell dysfunctions. Here, we demonstrated that plasmacytoid dendritic cells (pDCs) were a preferentially targeted leukocyte population early after LCMV infection in-vivo and that they represented a major leukocyte source of IFN- I. Remarkably, while conventional dendritic cell (cDC) IFN -I production was dependent on intrinsic viral replication, but uninfected pDCs produced IFN-I in a Toll-like receptor (TLR)-7 dependent manner. Moreover, continuous TLR stimulation was sufficient to down-regulate expression of a key pDC transcription factor, E2-2, and exhaust pDCs for IFN-I production. Treatment with a TLR-7 agonist during development caused pDC developmental and functional defects. Thus, the present study provides new insight into the mechanisms that lead to dendritic cell dysfunction during chronic viral infections and demonstrates that TLR stimulation alone is enough to cause functional defects in pDCs