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PNAS 96 (24): 13795-13800

Copyright © 1999 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids

Albrecht Lepple-Wienhues*,{dagger}, Claus Belka{ddagger}, Tilmann Laun*, Andreas Jekle*, Birgit Walter*, Ulrich Wieland*, Martina Welz*, Luzia Heil*, Jutta Kun*, Gillian Busch*, Michael Weller§, Michael Bamberg{ddagger}, Erich Gulbins*,¶, and Florian Lang*,¶

Departments of *Physiology I, {ddagger}Radiooncology, and §Neurology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany

Received for publication April 5, 1999.

Abstract: Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1/Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca2+ influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca2+ entry is lacking in CD95-defective lpr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca2+ influx, activation of the transcriptional regulator NFAT, and IL-2 synthesis. The block of CRAC by sphingomyelinase metabolites adds a function to the repertoire of the CD95 receptor inhibiting T cell activation signals.

{dagger} To whom reprint requests should be addressed. E-mail: alepplew{at}uni-tuebingen.de.

E.G. and F.L. contributed equally to this work.

Edited by Bertil Hille, University of Washington, Seattle, WA, and approved August 26, 1999

This paper was submitted directly (Track II) to the PNAS office.

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