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J. Biol. Chem., Vol. 278, Issue 49, 48633-48643, December 5, 2003

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Integrin ₂₁ Inhibits Fas-mediated Apoptosis in T Lymphocytes by Protein Phosphatase 2A-dependent Activation of the MAPK/ERK Pathway^*

Steve Gendron, Julie Couture, and Fawzi Aoudjit

From the Centre de Recherche en Immunologie et Rhumatologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL and Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada

The mechanisms by which T lymphocytes escape apoptosis during their activation are still poorly defined. In this study, we elucidated the intracellular signaling pathways through which ₁ integrins modulate Fas-mediated apoptosis in T lymphocytes. In experiments done in Jurkat T cells and activated peripheral blood T lymphocytes, engagement of ₂₁ integrin with collagen type I (Coll I) was found to significantly reduce Fas-induced apoptosis and caspase-8 activation; Annexin V binding and DNA fragmentation were reduced by 42 and 38%, respectively. We demonstrated that the protective action of Coll I does not require new protein synthesis but was dependent on the activation of the MAPK/Erk pathway. Furthermore, we found that activation of protein phosphatase 2A (PP2A) by Coll I was required for both Coll I-mediated activation of Erk, and inhibition of Fas-induced caspase-8 activation and apoptosis. Other ligands of ₁ integrins, fibronectin (Fbn), and laminin (Lam), did not sustain significant Erk activation and had no effect on Fas-induced apoptosis. Taken together, these results provide the first evidence of a PP2A-dependent activation of the MAPK/Erk pathway downstream of ₂₁ integrin, which has a functional role in regulating Fas-mediated apoptosis in T lymphocytes. As such, this study emphasizes the potential importance that Coll I interactions may have on the control of T lymphocyte homeostasis and their persistence in chronic inflammatory diseases.

Received for publication, May 16, 2003 , and in revised form, August 20, 2003.

^* This work was supported by grants from the Canadian Institutes of Health Research and from Fonds de Recherche en Santé du Québec (to F. A.). 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.

Recipient of a New Investigator scholarship award from the Canadian Arthritis Network. To whom correspondence should be addressed. Tel.: 418-656-4141 (ext. 46071); Fax: 418-654-2765; E-mail: fawzi.aoudjit{at}crchul.ulaval.ca.

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