UC San Diego

Plasmacytoid dendritic cells (pDCs) are a dendritic cell subset specialized to rapidly secrete copious amounts of Type I Interferon (IFN-I), a group of innate mediators that play key roles in antiviral immune defense and autoimmune diseases. Loss of pDC-derived IFN-I during chronic viral infection enhances susceptibility to secondary infection while excessive pDC IFN-I production contributes to autoimmune pathology, demonstrating the need for further investigation into the mechanisms of IFN- I regulation in pDCs. Through comparing gene expression profiles of pDCs and conventional (c) DCs, we found that Fyn, a member of the src-family kinases, and CD28, a prototypic T cell co-stimulatory receptor, were highly and selectively expressed in pDCs. Fyn acted as a positive regulator of pDC IFN-I and inflammatory cytokine production upon toll-like receptor (TLR) stimulation. In contrast, CD28 acted as a negative regulator of pDC IFN-I production but did not affect production of inflammatory cytokines or maturation. Our data suggests that Fyn and CD28 may play important roles in the regulation of pDC cytokine response during pathogenic challenge. These pathways may have evolved to fine-tune the magnitude of innate responses and to coordinate them with the adaptive immune response. Future studies will determine the mechanisms by which CD28 and Fyn regulate pDC cytokine production, including potential cross-talk with the Phosphoinositide 3-Kinase and TLR signaling pathways