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J. Biol. Chem., Vol. 278, Issue 29, 26983-26991, July 18, 2003

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The ₁ and ₃ Integrins Promote T Cell Receptor-mediated Cytotoxic T Lymphocyte Activation^*

From the ^aInstitute for Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland, the ^dLudwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland, ^cINSERM U563, CHU Purpan, 31059 Toulouse, France, the ^eKantonsspital, University of Basel, 4031 Basel, Switzerland, and the ^fCentre Pluridisciplinaire d'Oncologie, University of Lausanne Medical School, 1066 Epalinges, Switzerland

Recognition by CD8⁺ cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that ₁ and ₃ integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC·peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling.

Received for publication, March 17, 2003 , and in revised form, April 9, 2003.

^* 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.

^g Supported by grants from La Ligue contre le Cancer, l'Association de la Recherche contre le Cancer, and la Fondation pour la Recherche Médicale.

^h Supported by a grant of the Gabriella Giorgi-Cavaglieri Foundation and by the Swiss National Science Foundation (Grant 31-061960.00).

ⁱ Supported by the Swiss National Science Foundation (Grant 3100-061946.00).

^b To whom correspondence should be addressed. Tel.: 41-21-692-5745; Fax: 41-21-692-5705; E-mail: ma_doucey{at}hotmail.com.

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