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Modulation of T Cell Activation by Stomatin-Like Protein 2¹

Mark G. Kirchhof^*, Luan A. Chau^*, Caitlin D. Lemke^*, Santosh Vardhana, Peter J. Darlington^2,*, Maria E. Márquez^3,, Roy Taylor, Kamilia Rizkalla, Isaac Blanca, Michael L. Dustin and Joaquín Madrenas^4,*

^* FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, and Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada; Program in Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, New York, NY 10021; Instituto de Inmunologia, Universidad Central de Venezuela, Caracas, Venezuela; and Department of Pathology, London Health Sciences Centre, London, Ontario, Canada

T cell activation through the Ag receptor (TCR) requires sustained signaling from signalosomes within lipid raft microdomains in the plasma membrane. In a proteomic analysis of lipid rafts from human T cells, we identified stomatin-like protein (SLP)-2 as a candidate molecule involved in T cell activation through the Ag receptor. In this study, we show that SLP-2 expression in human primary lymphocytes is up-regulated following in vivo and ex vivo activation. In activated T cells, SLP-2 interacts with components of TCR signalosomes and with polymerized actin. More importantly, up-regulation of SLP-2 expression in human T cell lines and primary peripheral blood T cells increases effector responses, whereas down-regulation of SLP-2 expression correlates with loss of sustained TCR signaling and decreased T cell activation. Our data suggest that SLP-2 is an important player in T cell activation by ensuring sustained TCR signaling, which is required for full effector T cell differentiation, and point to SLP-2 as a potential target for immunomodulation.

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 grants from the Canadian Institutes of Health Research, the Kidney Foundation of Canada (Allison Knudsen Research Award), and the Multi-Organ Transplant Program of the London Health Sciences Centre (to J.M.); National Institutes of Health Grant R01-AI43549 (to M.L.D.); National Institutes of Health Training Grant T32-GM07308 (to S.V.); and FONACIT S12002000575 (to I.B.). M.G.K. is the recipient of a Canadian Institutes of Health Research MD/PhD studentship, and J.M. holds a Canada Research Chair in Immunobiology.

² Current address: Montreal Neurological Institute and Hospital, Room W010, 3801 University Street, Montreal, Quebec, H3A 2B4.

³ Current address: Laboratorio de Patología Celular y Molecular, Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Cientificas (IVIC), Caracas, Venezuela.

⁴ Address correspondence and reprint requests to Dr. Joaquín Madrenas, Robarts Research Institute, Room 2.05, P.O. Box 5015, 100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail address: madrenas{at}robarts.ca

⁵ Abbreviations used in this paper: IS, immunological synapse; LAT, linker for activation of T cells; PLC, phospholipase C; SEE, staphylococcal enterotoxin E superantigen; siRNA, small interfering RNA; SLP, stomatin-like protein; SPFH, stomatin/prohibitin/flotillins/HflK-HflC.