Src family kinase members Fyn and Lyn mediate type I interferon production by plasmacytoid dendritic cells. (INM7P.345)

Abstract

Abstract Plasmacytoid dendritic cells (pDCs) are the most powerful type I interferon (IFN-I) producing cells and are therefore important for antiviral defense and for autoimmune diseases such as systemic lupus erythematosus. However, the signaling factors that regulate pDC IFN-I production are not completely understood. Here we investigate the role of Src Family Kinases (SFKs), a family of non-receptor tyrosine kinases, in pDC responses to toll like receptor (TLR) stimulation. We first found that while human pDCs expressed mostly Lyn, mouse pDCs expressed both Lyn and Fyn, two members of SFKs. Importantly, we observed that pDCs from either Fyn or Lyn deficient mice exhibited impaired IFN-I and pro-inflammatory cytokine production after TLR-9 and TLR-7 stimulation, whereas no difference was observed in conventional DCs. Consistently, incubation of murine or human pDCs with a pan-SFKs inhibitor resulted in a dramatic ablation of pDC IFN-I and cytokine production in a dose dependent manner. Finally, treatment of a human pDC cell line (CAL-1) or pDCs from human peripheral blood with Bafetinib (a selective dual Bcr-Abl/Lyn inhibitor) profoundly ablated their IFN-I production after TLR stimulation. Taken together, our data indicate that the SFKs members Fyn and Lyn promote pDC IFN-I and pro-inflammatory cytokine production and suggest that Bafetinib could be considered as a therapeutic candidate for attenuating pDC responses in autoimmune diseases.