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CTL-Associated Antigen-4 Ligation Induces Rapid T Cell Polarization That Depends on Phosphatidylinositol 3-Kinase, Vav-1, Cdc42, and Myosin Light Chain Kinase¹

Bin Wei^*, Silvy da Rocha Dias^*, Hongyan Wang^* and Christopher E. Rudd^2,*,

^* Molecular Immunology Section, Department of Immunology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; and Cell Signalling Section, Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom

CTLA-4 can negatively regulate cytokine production and proliferation, increase motility, and override the TCR-induced stop-signal needed for stable T cell-APC conjugation. Despite this, little is known regarding whether CTLA-4 can alter T cell morphology and the nature of the signaling events that could account for this event. In this study, we demonstrate that anti-CTLA-4 and CD3/CTLA-4 induce rapid T cell polarization (i.e., within 15–30 min) with increases in lamellipodia, filopodia, and uropod formation. This was observed with anti-CTLA-4 and CD80-Ig ligation of CTLA-4, but not with anti-CD3 alone, or anti-CD3/CD28 coligation. Polarization required PI3K, the guanine nucleotide exchange factor Vav1, the GTP-binding protein Cdc42, as well as myosin L chain kinase. By contrast, a key downstream target of PI3K, protein kinase B, as well as Rho kinase and RhoA, were not needed. Our results demonstrate that CTLA-4 is a potent activator T cell polarization needed for motility, and this process involves specific set of signaling proteins that might contribute to coreceptor regulation of T cell function.

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 from a grant from the Wellcome Trust, London. C.E.R. is the recipient of a Principal Research Fellow Award.

² Address correspondence and reprint requests to Dr. Christopher E. Rudd, Cambridge University, Tennis Court Road, Cambridge, U.K. E-mail address: cer51{at}cam.ac.uk

³ Abbreviations used in this paper: PIP₃, phosphatidylinositol 3,4,5-trisphosphate; GEF, guanine nucleotide exchange factor; GSK-3, glycogen synthase kinase-3; HA, hemagglutinin; MLCK, myosin L chain kinase; PH, pleckstrin homology; PKB, protein kinase B; ROCK, Rho kinase.

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