CD95 engagement releases calcium from intracellular stores of long term activated, apoptosis-prone gammadelta T cells.
Engagement of the CD95 (Apo-1, Fas) membrane receptor is known to induce apoptosis in a variety of sensitive cells, even in the absence of extracellular Ca2+. The signal transduction events implicated in this pathway are poorly understood. We have recently characterized normal human Vgamma9/Vdelta2+ T cell clones that maintain similar levels of CD95 membrane expression throughout the culture. Here we show that 3 wk of culture after in vitro restimulation are necessary for the cells both to die and to acquire the ability to mobilize intracellular Ca2+ upon CD95 ligation. Buffering of intracellular Ca2+ by accumulation of the chelator 1,2-bis(2-amino phenoxy)ethane-N,N,N1,N-tetraacetic acid protects from CD95-triggered apoptosis, suggesting that the two phenomena are causally related. As intracellular Ca2+ release by inhibition of endoplasmic reticulum ATPases induces apoptosis in both recently and long term activated gamma delta cells, the molecular regulation of activation-dependent apoptosis is likely to involve events upstream of CD95-dependent Ca2+ release. The CD95-triggered increase in the intracellular Ca2+ concentration depends on depletion of the same intracellular Ca2+ stores mobilized by ligation of the TCR, and Ca2+ release does not depend on inositol 1,4,5-trisphosphate generation.
Rovere
P
P
Second Department of Medicine, Laboratory of Immunology and Receptor Biochemistry Unit, University of Milan School of Medicine, Milan, Italy.
Clementi
E
E
Ferrarini
M
M
Heltai
S
S
Sciorati
C
C
Sabbadini
M G
MG
Rugarli
C
C
Manfredi
A A
AA
D017209:Apoptosis; D002118:Calcium / Q000502:physiology*; D002451:Cell Compartmentation; D002478:Cells, Cultured; D002999:Clone Cells; D006706:Homeostasis; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008213:Lymphocyte Activation; D011940:Receptor Aggregation; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D019014:fas Receptor / Q000502:physiology*
D016692:Receptors, Antigen, T-Cell, gamma-delta; D019014:fas Receptor; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium