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J. Biol. Chem., Vol. 279, Issue 53, 55376-55384, December 31, 2004

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Engaged and Bystander T Cell Receptors Are Down-modulated by Different Endocytotic Pathways^*

Alicia Monjas, Andrés Alcover¶, and Balbino Alarcón||

From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain and the ^¶Unité de Biologie des Interactions Cellulaires, CNRS URA 2582, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France

T cell antigen receptor (TCR) engagement by stimulatory antibodies or its major histocompatibility complexantigen ligand results in its down-modulation from the cell surface, a phenomenon that is thought to play a role in T cell desensitization. However, TCR engagement results in the down-modulation not only of the engaged receptors but also of non-engaged bystander TCRs. We have investigated the mechanisms that mediate the down-modulation of engaged and bystander receptors and show that co-modulation of the bystander TCRs requires protein-tyrosine kinase activity and is mediated by clathrin-coated pits. In contrast, the down-modulation of engaged TCRs is independent of protein-tyrosine kinases and clathrin pits, suggesting that this process is mediated by an alternate mechanism. Indeed, down-modulation of engaged TCRs appears to depend upon lipid rafts, because cholesterol depletion with methyl--cyclodextrin completely blocks this process. Thus, two independent pathways of internalization are involved in TCR down-modulation and act differentially on directly engaged and bystander receptors. Finally, we propose that although both mechanisms coexist, the predominance of one or the other mechanisms will depend on the dose of ligand.

Received for publication, August 16, 2004 , and in revised form, October 14, 2004.

^* This work was supported by Grant SAF2002-03589 from the Comisión Interministerial de Ciencia y Tecnología, Grant 08.3/0030/2001 from the Comunidad de Madrid, and the institutional support of Fundación Areces to the Centro de Biologia Molecular Severo Ochoa. 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.

A fellow of the Beca de Formación en Investigación 00/9129 from Instituto de Salud Carlos III.

^|| To whom correspondence should be addressed: Centro de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Tel.: 34-914978458; E-mail: balarcon{at}cbm.uam.es.

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