HUMAN T-CELLS REQUIRE IL-2 BUT NOT G(1) S TRANSITION TO ACQUIRE SUSCEPTIBILITY TO FAS-MEDIATED APOPTOSIS/

The interaction between Fas ligand and Fas, both expressed on activate d T cells, is the major pathway in the regulation of activation-induce d cell death, However, activated T cells that express membrane Fas are initially resistant to anti-fas-induced apoptosis and become suscepti ble 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- las-mediated apoptosis. Interference with the IL-2 pathway was achieve d 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 t o 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, wherea s Fas-mediated apoptosis does not develop in the presence of inhibitor s of IL-2 production or signaling, While the addition of rlL-2 reverse d the inhibitory effect of cyclosporin A and FK506, the addition of rl L-4, rlL-7, or rIFN-gamma did not, although these cytokines induced pr ogression into the S phase of the cell cycle, Aphidicolin-treated acti vated T cells that do not progress into the S phase were susceptible t o Fas-mediated apoptosis, Therefore, Fas-mediated apoptosis is control led by signals generated by IL-2 in agreement with the reported altera tion of apoptosis in mice deficient in ii-a or IL-2R.