IL-4 IS ABLE TO REVERSE THE CD2-MEDIATED NEGATIVE APOPTOTIC SIGNAL TOCD4(-) CD8(-) ALPHA-BETA AND OR GAMMA-DELTA T-LYMPHOCYTES/

Activation of immature thymocytes or transformed T lymphocytes via T-c ell receptor (TCR)/CD3 signalling can induce programmed cell death (ap optosis). Recent data indicate that anti-CD3/TCR monoclonal antibodies (mAb) also trigger apoptosis in activated (but not resting) mature pe ripheral blood T lymphocytes. Here we report that triggering of restin g CD4(-) CD8(-) TCR alpha beta(+) and/or TCR gamma delta(+) via the al ternative CD2-dependent activation pathway is able to induce programme d cell death. A pair of mitogenic anti-CD2 mAb provoked a dramatic ris e in [Ca2+](i) that was almost entirely sustained by extracellular flu xes, and the inhibition of membrane [Ca2+/Mg2+] ATPase. The resulting endonuclease activation was able to induce DNA fragmentation, as revea led by propidium iodide staining and gel electrophoresis. Induction of apoptosis was prevented by the presence of interleukin-4 (IL-4) as we ll as by endonuclease inactivation with 100 mu M ZnCl2, but enhanced b y the contemporary block of protein kinase C. Thus it seems that in re sting T lymphocytes the strong calcium signal delivered by the alterna tive CD2 activation pathway may act as a negative apoptotic signal in both alpha beta and gamma delta T cells with low (non-major histocompa tibility complex restricted) antigenic affinity, so limiting the exten sion of polyclonal T-cell growth.