(Experimental Medicine)

ii SHIP (SH2-containing inositol 5′-phosphatase) is a hematopoietic restricted enzyme responsible for the hydrolysis of the phosphatidylinositol 3-kinase-generated second messenger PI-3,4,5-P3 to PI-3,4-P2 and, thereby, negatively regulates cell survival, proliferation and differentiation. Herein, we demonstrate a role for SHIP in the differentiation and function of dendritic cells (DCs). We found that SHIP restrains in vitro generation and survival of bone marrow derived DCs cultured with granulocyte macrophage colony stimulating factor (GM-CSF) or fms-like tyrosine kinase 3 ligand (Flt3L). These results are consistent with the in vivo finding that SHIP-deficient mice have increased numbers of splenic DCs. We provide evidence that Ship-/- GM-CSF-derived DCs (GM-DCs) have impaired ability to activate T cells – a defect associated with deficient DC maturation and interleukin-12 (IL-12) production in response to Toll-like receptor (TLR) agonists. Reduced antigen (Ag)-specific T cell activation was associated with defective TH1 cell induction in vitro and in vivo. SHIP’s role is mor