SHIP Is Required for Dendritic Cell Maturation
SHIP Is Required for Dendritic Cell Maturation
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DOI：
10.4049/jimmunol.0903170
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发表时间：
2010-03-15
影响因子：
4.4
通讯作者：
Krystal, Gerald
中科院分区：
文献类型：
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作者：
Antignano, Frann;Ibaraki, Mariko;Krystal, Gerald
尽管几个研究小组已经研究了SHIP在巨噬细胞（M phi）发育和功能中的作用，但对SHIP对树突状细胞（DC）的产生、成熟和先天免疫激活的贡献知之甚少。我们在此表明，SHIP负调控体外和体内从骨髓前体产生DC，如通过增强的来自SHIP-/- GM-CSF培养物的DC扩增以及SHIP缺陷小鼠脾脏中DC数量的增加所示。然而，有趣的是，这些SHIP-/-DC表现出相对不成熟的表型，并且在TLR配体刺激后比野生型DC分泌实质上更低水平的IL-12。这反过来又导致体外和体内Ag特异性T细胞增殖和Th 1细胞应答的刺激显著降低。SHIP-/-DC的这种不成熟表型可以用PI 3 K抑制剂LY 294002和渥曼青霉素逆转，这表明SHIP通过降低PI 3 K第二信使磷脂酰肌醇-3，4，5-三磷酸盐的水平来促进DC成熟。这些结果与SHIP是GM-CSF衍生的DC产生的负调节剂，但却是GM-CSF衍生的DC成熟和功能的正调节剂一致。免疫学杂志，2010，184：2805-2813.
Although several groups have investigated the role of SHIP in macrophage (M phi) development and function, SHIP's contribution to the generation, maturation, and innate immune activation of dendritic cells (DCs) is poorly understood. We show herein that SHIP negatively regulates the generation of DCs from bone marrow precursors in vitro and in vivo, as illustrated by the enhanced expansion of DCs from SHIP-/- GM-CSF cultures, as well as increased numbers of DCs in the spleens of SHIP-deficient mice. Interestingly, however, these SHIP-/- DCs display a relatively immature phenotype and secrete substantially lower levels of IL-12 after TLR ligand stimulation than wild type DCs. This, in turn, leads to a dramatically reduced stimulation of Ag-specific T cell proliferation and Th1 cell responses in vitro and in vivo. This immature phenotype of SHIP-/- DCs could be reversed with the PI3K inhibitors LY294002 and wortmannin, suggesting that SHIP promotes DC maturation by reducing the levels of the PI3K second messenger phosphatidylinositol-3,4,5-trisphosphate. These results are consistent with SHIP being a negative regulator of GM-CSF-derived DC generation but a positive regulator of GM-CSF-derived DC maturation and function. The Journal of Immunology, 2010, 184: 2805-2813.