Tassi Ilaria, Cella Marina, Gilfillan Susan, Turnbull Isaiah, Diacovo Thomas G, Penninger Josef M, Colonna Marco
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Immunity. 2007 Aug;27(2):214-27. doi: 10.1016/j.immuni.2007.07.014.
Phosphoinositide 3-kinases (PI-3Ks) are key enzymes for cell development, activation, and survival. Here we showed that PI-3K class IB and class IA catalytic subunits, p110gamma and p110delta, played a crucial role in the development and functions of murine NK cells. p110gamma deficiency and impairment of G protein-coupled receptor (GPRC) signaling prevented full NK cell maturation. Concomitant loss of p110gamma and p110delta exacerbated this defect, resulting in a very small population of NK cells with a highly immature phenotype in the bone marrow and periphery. Moreover, combined p110gamma and p110delta signals were required for cytotoxicity and activation of the kinase ERK during NK cell-target cell interaction. p110gamma played a major role in receptor-induced interferon-gamma (IFN-gamma) production through a pathway that involved the kinase ERK and 5-Lipoxigenase, which most likely generates lipid mediators activating GPRCs. Conversely, PI3Ks negatively regulated interleukin-12 (IL-12) and IL-18-induced IFN-gamma by modulating p38 kinase activation. Our data shed light on the multiple intersecting pathways through which PI3Ks control NK cell-mediated innate responses.
磷酸肌醇-3激酶(PI-3Ks)是细胞发育、激活和存活的关键酶。在此我们表明,PI-3K IB类和IA类催化亚基p110γ和p110δ在小鼠自然杀伤(NK)细胞的发育和功能中起关键作用。p110γ缺陷以及G蛋白偶联受体(GPRC)信号受损会阻碍NK细胞完全成熟。p110γ和p110δ同时缺失会加剧这一缺陷,导致骨髓和外周中具有高度未成熟表型的NK细胞数量极少。此外,在NK细胞与靶细胞相互作用过程中,细胞毒性以及激酶细胞外信号调节激酶(ERK)的激活需要p110γ和p110δ信号共同作用。p110γ在受体诱导的γ干扰素(IFN-γ)产生中起主要作用,其途径涉及激酶ERK和5-脂氧合酶,后者很可能生成激活GPRCs的脂质介质。相反,PI3Ks通过调节p38激酶激活来负向调节白细胞介素-12(IL-12)和IL-18诱导的IFN-γ。我们的数据揭示了PI3Ks控制NK细胞介导的先天性免疫反应的多个交叉途径。