BCAP promotes TLR-induced IFNα in plasmacytoid DC

Abstract

Abstract Systemic lupus erythematosus (SLE) severity is correlated with elevated serum levels of type I interferons (IFN), specifically IFNα. pDC are important in the pathogenesis and etiology of SLE due to their ability to produce large amounts of IFNα. TLR-induced INFα production in pDC occurs upon RNA or DNA recognition by TLR7 or 9 respectively. Two events are necessary to induce IFNα by pDC: 1) the binding of ligand to TLR7 or TLR9 within the early endosome, and 2) the phosphorylation and nuclear translocation of the transcription factor IRF7. TLR7 and TLR9-induced IRF7 translocation to the nucleus and subsequent IFN production by pDC is dependent on phosphatidylinositol-3 kinase (PI3K), but how PI3K regulates this process remains undefined. The PI3K pathway is important for many cellular processes, but it is unknown how PI3K activation is induced by TLR signaling in pDC. Our lab showed that the cytosolic signaling adapter B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation in macrophages, resulting in inhibition of TLR-induced inflammatory cytokines. In contrast, here we show BCAP promotes TLR7 and TLR9-induced type I IFN production in pDC. We found that BCAP was required for optimal TLR9 and TLR7-induced IFNα production in pDC grown from BM in vitro in presence of Flt3L or sorted directly ex vivo, while inflammatory cytokine levels were less affected. Strikingly, BCAP−/− mice produced much less serum IFNα early after injection of TLR9 agonist than WT mice, consistent with a pDC IFNα defect. BCAP−/−pDC have reduced AKT phosphorylation when stimulated with TLR agonists, showing BCAP activates PI3K downstream of TLR in pDC. Overall, we show a novel role for BCAP in regulating IFNα production in pDC.