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Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node¹

Melanie P. Matheu^*, Jonathan A. Deane, Ian Parker^*,, David A. Fruman^2,, and Michael D. Cahalan^2,3,*,

^* Department of Physiology and Biophysics, Department of Molecular Biology and Biochemistry, Department Neurobiology and Behavior, and Center for Immunology, University of California, Irvine, California 92697

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 p85 and p85 also exhibited reduced velocities, with the magnitude of reduction depending upon both cell type and isoform specificity. B cells deficient in p85 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 p85 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants GM41514 (to M.D.C.), AI50831 (to D.A.F.), and GM-48071 (to I.P.) and by National Institutes of Health Kirchstein Fellowship AI-64128 (to M.P.M.).

² D.A.F. and M.D.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Michael D. Cahalan, Department of Physiology and Biophysics, University of California, Irvine, CA 92697-4561. E-mail address: mcahalan{at}uci.edu

⁴ Abbreviations used in this paper: PtdIns(3,4,5)P₃, phosphatidylinositol-3,4,5-trisposphate; CMTMR, 5-(and-6)-(((4-chloromethyl) benzol) amino)tetramethylrhodamine); DOCK2, dedicator of cytokinesis 2; KO, knockout; SDF-1, stromal cell-derived factor-1; WMN, wortmannin.

⁵ The online version of this article contains supplemental material.

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The JI 2007 179: 2033-2034. [Full Text]  

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