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The role of SHIP in dendritic cell differentiation and function Antignano, Frann Lillis

Abstract

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 more restricted in Flt3L-derived DCs (FL-DCs) since the functional abnormalities of Ship-/- FL-DCs, leading to reduced DC maturation and Ag-specific T cell proliferation, are limited to MyD88-independent TLR activation pathways. Thus, we conclude that the function of SHIP in DC biology depends on the derivation context and the nature of the activating pathogen. Next, we evaluated the role of Ship-/- DCs in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis previously thought to primarily depend on a TH1-mediated immune response. We found that SHIP-deficient mice develop EAE despite reduced DC-induced T cell activation. Notwithstanding evidence of a disease suppressive environment, we show evidence that Ship-/- mice have robust clinical symptoms after EAE induction resulting from enhanced production of Ag-specific IgMs in vivo. In addition to T cell activation, under certain conditions DCs may suppress T cell proliferation using a variety of mechanisms. We show Ship-/- GM-DCs, despite expressing high levels of the T cell suppressing enzyme arginase 1, do not have enhanced suppressive ability. Intriguingly, in contrast to WT GM-DCs, we found that Ship-/- GM-DCs do not use interferon gamma-induced nitric oxide production to suppress T cell proliferation but rather an alternative contact-dependent suppressive mechanism.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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