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Hyaluronan Induces Cell Death in Activated T Cells through CD44¹

Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada

In the immune system, leukocyte activation induces CD44 to bind hyaluronan, a component of the extracellular matrix. Here we used gain and loss of hyaluronan-binding mutants of CD44 to examine the consequence of hyaluronan binding in T cells. Jurkat T cells transfected with CD44 mutated at S180, which prevented the addition of chondroitin sulfate, displayed constitutively high levels of hyaluronan binding. These cells were more susceptible to activation-induced cell death, whereas cells expressing a CD44 mutant unable to bind hyaluronan (R41A) were resistant to cell death. In TCR or PMA activated Jurkat T cells, hyaluronan induced rapid cell death. This depended on the level of hyaluronan binding by the cell, and the amount and size of hyaluronan. High molecular mass hyaluronan had the greatest effect and cell death occurred independently of Fas and caspase activation. In splenic T cells, high hyaluronan binding occurred in a subpopulation of cells undergoing activation-induced cell death. In addition, hyaluronan induced cell death in 10% of reactivated splenic T cells when Fas-dependent apoptosis was prevented by Ab blocking or in Fas negative MRL/lpr T cells. This demonstrates that hyaluronan can induce cell death in activated, high hyaluronan binding T cells via a Fas-independent mechanism.

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 This work was supported by a grant from the Canadian Institutes of Health Research. B.R. was funded by the Heart and Stroke Foundation of Canada.

² Address correspondence and reprint requests to Dr. Pauline Johnson, Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3, Canada. E-mail address: pauline{at}interchange.ubc.ca

³ Abbreviations used in this paper: HA, hyaluronan; AICD, activation-induced cell death; β-D-xyloside, p-nitrophenyl β-D-xylopyranoside; CS, chondroitin sulfate; DAPI, 4',6-diamidino-2-phenylindole; FasL, Fas ligand; Fl-HA, fluorescein-conjugated HA; PI, propidium iodide; PS, phosphatidylserine.

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