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* Program in Cellular and Molecular Biology, University of Wisconsin, Madison, WI 53706; and
Department of Pediatrics and Department of Pharmacology, University of Wisconsin, Madison, WI 53706
The leukocyte integrin LFA-1 plays a critical role in T cell trafficking and T cell adhesion to APCs. It is known that integrin-mediated adhesion is regulated by changes in integrin ligand-binding affinity and valency through inside-out signaling. However, the molecular mechanisms involved in TCR-mediated LFA-1 regulation are not well understood. In this study, we show that the cytoskeletal protein talin1 is required for TCR-mediated activation of LFA-1 through regulation of LFA-1 affinity and clustering. Depletion of talin1 from human T cells by small interfering RNAs impairs TCR-induced adhesion to ICAM-1 and T cell-APC conjugation. TCR-induced LFA-1 polarization, but not actin polarization, is defective in talin1-deficient T cells. Although LFA-1 affinity is also reduced in talin1-deficient T cells, rescue of LFA-1 affinity alone is not sufficient to restore LFA-1 adhesive function. Together, our findings indicate that TCR-induced up-regulation of LFA-1-dependent adhesiveness and resulting T cell-APC conjugation require talin1.
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 R01CA85862-06 (to A.H.), T32 AG20013 (to W.T.N.S.), and T32GM07215-25 (to S.J.F.).
2 Current address: Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037.
3 Address correspondence and reprint requests to Dr. Anna Huttenlocher, 1300 University Avenue, Room 2765, Madison, WI 53706. E-mail address: huttenlocher{at}wisc.edu
4 Abbreviations used in this paper: PBT, peripheral blood T; siRNA, small interfering RNA; EGFP, enhanced GFP; PKC, protein kinase C; RT, room temperature; SEE, staphylococcal enterotoxin E; TRITC, tetramethylrhodamine isothiocyanate.
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