BCAP regulation of TLR-induced IFNa in plasmacytoid DC

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 DESCRIPTION (provided by applicant): pDC are important mediators for the pathogenesis and etiology of systemic lupus erythematosus (SLE) due to their ability to produce large amounts of IFNα upon activation. This is highlighted by recent studies directly linking pDC to progression of SLE disease using mouse models with reduced pDC numbers. TLR-induced IFNα production in pDC occurs upon DNA or RNA recognition by TLR7 or TLR9 respectively. My preliminary data suggest that B cell adaptor protein (BCAP) promotes TLR9-induced IFNα induction. We found that BCAP is required for optimal IFNα induction while inflammatory cytokine levels are less affected upon TLR9 stimulation. BCAP is a signaling adaptor protein molecule expressed in many hematopoietic cells and is capable of recruiting PI3K through its four YxxM motifs. Our lab has shown in macrophages that BCAP interacts with two signaling proteins known to regulate pDC IFNα production, phosphatidylinositol-3 kinase (PI3K) and DOCK2. Recent data has shown that TLR-induced IRF7 translocation to the nucleus and subsequent IFNα production by pDC is dependent on PI3K and on DOCK2 dependent IKKα phosphorylation. Upon TLR stimulation, BCAP-/- pDC have a similar phenotype to PI3K inhibited and DOCK2-deficient pDC, suggesting that BCAP may regulate TLR-induced IFNα through one or both of these signaling pathways. DOCK2 is an important Rac guanine nucleotide exchange factor (GEF), which is known to control migration and IFNα production in pDC. The PI3K pathway is important for many cellular processes, such as proliferation, phagocytosis and vesicular trafficking. It is not known how PI3K activation is induced by TLR signaling in pDCs, although our lab has shown in macrophages that B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation. Therefore, in this proposal, we seek to test the hypothesis that BCAP regulates TLR9- induced IFNα production via PI3K and/or DOCK2 activation in pDC, to determine the mechanism by which this occurs, and to test the hypothesis that BCAP in pDC promotes lupus-like disease in an in vivo mouse model.