Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids.
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 Ca(2+) influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca(2+) 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 Ca(2+) 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.
Lepple-Wienhues
A
A
Department of Physiology I, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. alepplew@uni-tuebingen.de
Belka
C
C
Laun
T
T
Jekle
A
A
Walter
B
B
Wieland
U
U
Welz
M
M
Heil
L
L
Kun
J
J
Busch
G
G
Weller
M
M
Bamberg
M
M
Gulbins
E
E
Lang
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002518:Ceramides / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002518:Ceramides; D013107:Sphingolipids; D019014:fas Receptor; D013108:Sphingomyelin Phosphodiesterase; D002118:Calcium