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J. Biol. Chem., Vol. 281, Issue 35, 25184-25194, September 1, 2006

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CCL5-CCR5-mediated Apoptosis in T Cells

REQUIREMENT FOR GLYCOSAMINOGLYCAN BINDING AND CCL5 AGGREGATION^*

Thomas T. Murooka¹, Mark M. Wong, Ramtin Rahbar¹, Beata Majchrzak-Kita, Amanda E. I. Proudfoot, and Eleanor N. Fish²

From the Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario, M5G 2M1, Canada, and Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland

CCL5 (RANTES (regulated on activation normal T cell expressed and secreted)) and its cognate receptor, CCR5, have been implicated in T cell activation. CCL5 binding to glycosaminoglycans (GAGs) on the cell surface or in extracellular matrix sequesters CCL5, thereby immobilizing CCL5 to provide the directional signal. In two CCR5-expressing human T cell lines, PM1.CCR5 and MOLT4.CCR5, and in human peripheral blood-derived T cells, micromolar concentrations of CCL5 induce apoptosis. CCL5-induced cell death involves the cytosolic release of cytochrome c, the activation of caspase-9 and caspase-3, and poly(ADP-ribose) polymerase cleavage. CCL5-induced apoptosis is CCR5-dependent, since native PM1 and MOLT4 cells lacking CCR5 expression are resistant to CCL5-induced cell death. Furthermore, we implicate tyrosine 339 as a critical residue involved in CCL5-induced apoptosis, since PM1 cells expressing a tyrosine mutant receptor, CCR5Y339F, do not undergo apoptosis. We show that CCL5-CCR5-mediated apoptosis is dependent on cell surface GAG binding. The addition of exogenous heparin and chondroitin sulfate and GAG digestion from the cell surface protect cells from apoptosis. Moreover, the non-GAG binding variant, (⁴⁴AANA⁴⁷)-CCL5, fails to induce apoptosis. To address the role of aggregation in CCL5-mediated apoptosis, nonaggregating CCL5 mutant E66S, which forms dimers, and E26A, which form tetramers at micromolar concentrations, were utilized. Unlike native CCL5, the E66S mutant fails to induce apoptosis, suggesting that tetramers are the minimal higher ordered CCL5 aggregates required for CCL5-induced apoptosis. Viewed altogether, these data suggest that CCL5-GAG binding and CCL5 aggregation are important for CCL5 activity in T cells, specifically in the context of CCR5-mediated apoptosis.

Received for publication, May 19, 2006 , and in revised form, June 29, 2006.

^* 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 Supported by a grant by the Canadian Institutes of Health Research.

² To whom correspondence should be addressed: Division of Cellular and Molecular Biology, Toronto General Research Institute, Canadian Blood Services Bldg. 67 College St., Rm. 4-424, Toronto, Ontario, M5G 2M1 Canada. Tel.: 416-340-5380; Fax: 416-340-3453; E-mail: en.fish{at}utoronto.ca.

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