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J. Biol. Chem., Vol. 280, Issue 8, 6969-6985, February 25, 2005

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Galectin-1 Sensitizes Resting Human T Lymphocytes to Fas (CD95)-mediated Cell Death via Mitochondrial Hyperpolarization, Budding, and Fission^*

Paola Matarrese, Antonella Tinari, Elisabetta Mormone, Germán A. Bianco¶, Marta A. Toscano¶, Barbara Ascione, Gabriel A. Rabinovich¶||**, and Walter Malorni||

From the Department of Drug Research and Evaluation, and Technology and Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome 00161, Italy and the ^¶Laboratory of Inmunogenetics, Hospital de Clínicas José de San Martín, Faculty of Medicine, University of Buenos Aires, Avenida Córdoba 2351, 3er Piso, C1120 Buenos Aires, Argentina

Galectins have emerged as a novel family of immunoregulatory proteins implicated in T cell homeostasis. Recent studies showed that galectin-1 (Gal-1) plays a key role in tumor-immune escape by killing antitumor effector T cells. Here we found that Gal-1 sensitizes human resting T cells to Fas (CD95)/caspase-8-mediated cell death. Furthermore, this protein triggers an apoptotic program involving an increase of mitochondrial membrane potential and participation of the ceramide pathway. In addition, Gal-1 induces mitochondrial coalescence, budding, and fission accompanied by an increase and/or redistribution of fission-associated molecules h-Fis and DRP-1. Importantly, these changes are detected in both resting and activated human T cells, suggesting that Gal-1-induced cell death might become an excellent model to analyze the morphogenetic changes of mitochondria during the execution of cell death. This is the first association among Gal-1, Fas/Fas ligand-mediated cell death, and the mitochondrial pathway, providing a rational basis for the immunoregulatory properties of Gal-1 in experimental models of chronic inflammation and cancer.

Received for publication, August 25, 2004 , and in revised form, November 3, 2004.

^* This work was supported by grants from the Ministry of Health and National Research Council (to W. M.) and by grants from Wellcome Trust, Antorchas Foundation, Sales Foundation, Ministry of Health (Carrillo-Oñativia Fellowship), and University of Buenos Aires Grant UBACYT M091 (to G. A. R.). 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.

^|| These authors contributed equally to this work.

^** Member of CONICET (Consejo Nacional de Investigaciones Científicas y Tecnológias).

To whom correspondence should be addressed: Dept. of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanitá, Viale Regina Elena 299, Rome 00161, Italy. Tel.: 39-06-4990-2905; Fax: 39-06-4990-3691; E-mail: malorni{at}iss.it.

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