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First published online 13 December 2005
doi: 10.1242/jcs.02722

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ß2-chimaerin provides a diacylglycerol-dependent mechanism for regulation of adhesion and chemotaxis of T cells

¹ Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Cantoblanco, E-28049 Madrid, Spain
² Department of Immunology, Centro de Investigaciones Biológicas/CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain
³ Department of Molecular Pharmacology, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, USA

^* Author for correspondence (e-mail: imerida{at}cnb.uam.es)

Accepted 3 October 2005

The small GTPase Rac contributes to regulation of cytoskeletal rearrangement during chemokine-induced lymphocyte adhesion and migration in a multi-step process that is very precisely coordinated. Chimaerins are Rac1-specific GTPase-activating proteins of unknown biological function, which have a canonical diacylglycerol C1-binding domain. Here we demonstrate endogenous expression of ß2-chimaerin in T lymphocytes and study the functional role of this protein in phorbol ester and chemokine (CXCL12)-regulated T-cell responses. We used green fluorescent protein-tagged ß2-chimaerin and phorbol ester stimulation to investigate changes in protein localization in living lymphocytes. Our results demonstrate that active Rac cooperates with C1-dependent phorbol ester binding to induce sustained GFP-ß2-chimaerin localization to the membrane. Subcellular distribution of GFP ß2-chimaerin in living cells showed no major changes following CXCL12 stimulation. Nonetheless Rac1-GTP levels were severely inhibited in GFP-ß2-chimaerin-expressing cells, which displayed reduced CXCL12-induced integrin-dependent adhesion and spreading. This effect was dependent on chimaerin GTPase-activating protein function and required diacylglycerol generation. Whereas ß2-chimaerin overexpression decreased static adhesion, it enhanced CXCL12-dependent migration via receptor-dependent diacylglycerol production. These studies demonstrate that ß2-chimaerin provides a novel, diacylglycerol-dependent mechanism for Rac regulation in T cells and suggest a functional role for this protein in Rac-mediated cytoskeletal remodeling.

Key words: Diacylglycerol, C1 domain, Chemokines, Immune response, Rac GTPases

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