Matheu Melanie P, Deane Jonathan A, Parker Ian, Fruman David A, Cahalan Michael D
Department of Physiology and Biophysics, University of California, Irvine, California 92697, USA.
J Immunol. 2007 Aug 15;179(4):2261-9. doi: 10.4049/jimmunol.179.4.2261.
Recruitment of PI3K to the cell membrane is an indispensable step in normal lymphocyte proliferation and activation. In this study we identify PI3K as an important signaling molecule for maintaining basal T and B lymphocyte motility and homing in the intact lymph node. Pharmacological inhibition of PI3K catalytic isoforms exerted broad effects on basal lymphocyte motility, including changes in homing kinetics, localization of B cells within the lymph node, and reduced cell velocities. Lymphocytes deficient in either or both of the class IA PI3K regulatory subunits p85alpha and p85beta also exhibited reduced velocities, with the magnitude of reduction depending upon both cell type and isoform specificity. B cells deficient in p85alpha exhibited gross morphological abnormalities that were not evident in cells treated with a PI3K inhibitor. Our results show, for the first time, that class IA PI3Ks play an important role in regulating basal lymphocyte motility and that p85alpha regulatory subunit expression is required to maintain B cell morphology in a manner independent of PI3K catalytic function. Moreover, we demonstrate distinct roles for catalytic domain function and class IA PI3K regulatory domain activity in lymphocyte motility, homing, and homeostatic localization of mature resting B cells.
PI3K募集至细胞膜是正常淋巴细胞增殖和激活过程中不可或缺的一步。在本研究中，我们确定PI3K是维持完整淋巴结中基础T和B淋巴细胞运动性及归巢的重要信号分子。PI3K催化亚型的药理学抑制对基础淋巴细胞运动性产生广泛影响，包括归巢动力学变化、B细胞在淋巴结内的定位以及细胞速度降低。缺乏IA类PI3K调节亚基p85α和p85β其中之一或两者的淋巴细胞也表现出速度降低，降低幅度取决于细胞类型和亚型特异性。缺乏p85α的B细胞表现出明显的形态异常，在用PI3K抑制剂处理的细胞中未观察到这种异常。我们的结果首次表明，IA类PI3K在调节基础淋巴细胞运动性中起重要作用，并且p85α调节亚基的表达对于以独立于PI3K催化功能的方式维持B细胞形态是必需的。此外，我们证明了催化结构域功能和IA类PI3K调节结构域活性在成熟静止B细胞的淋巴细胞运动性、归巢和稳态定位中的不同作用。
