Human T cells require IL-2 but not G1/S transition to acquire susceptibility to Fas-mediated apoptosis.
The interaction between Fas ligand and Fas, both expressed on activated T cells, is the major pathway in the regulation of activation-induced cell death. However, activated T cells that express membrane Fas are initially resistant to anti-Fas-induced apoptosis and become susceptible only after proliferation in vitro. Since IL-2 is known to regulate activation-induced cell death, we studied the effect of IL-2 on anti-Fas-mediated apoptosis. Interference with the IL-2 pathway was achieved by 1) inhibition of cytokine synthesis using cyclosporin A or FK506, 2) neutralization of IL-2 by anti-IL-2 Ab, 3) inhibition of binding to IL-2R by CD25 mAb, and 4) blocking of IL-2R signaling by rapamycin. We show that Fas expression is independent of the IL-2 pathway, whereas Fas-mediated apoptosis does not develop in the presence of inhibitors of IL-2 production or signaling. While the addition of rIL-2 reversed the inhibitory effect of cyclosporin A and FK506, the addition of rIL-4, rIL-7, or rIFN-gamma did not, although these cytokines induced progression into the S phase of the cell cycle. Aphidicolin-treated activated T cells that do not progress into the S phase were susceptible to Fas-mediated apoptosis. Therefore, Fas-mediated apoptosis is controlled by signals generated by IL-2 in agreement with the reported alteration of apoptosis in mice deficient in IL-2 or IL-2R.
INSERM Unit 80 University Claude Bernard, Hospital E. Herriot, Lyon, France.
S
S
Fournel
L
L
Genestier
E
E
Robinet
M
M
Flacher
J P
JP
Revillard
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004198:Disease Susceptibility; D016193:G1 Phase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000032:analysis* / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016196:S Phase / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019014:fas Receptor