IL-12 decreases activation-induced cell death in human naive Th cells costimulated by intercellular adhesion molecule-1. I. IL-12 alters caspase processing and inhibits enzyme function

Th cells can receive costimulatory signals through the LFA-1/ICAM-1 accesso ry pathway that are sufficient to induce early Th cell proliferation, but n ot subsequent cell expansion and maintenance of cell viability. To investig ate the regulatory role for IL-12 in ICAM-1-mediated costimulation, human n aive Th cells were stimulated with coimmobilized anti-CD3 mAb and ICAM-1 Ig in the presence or absence of IL-12. The ICAM-1-mediated costimulatory sig nals in this model resulted in early Th cell proliferation followed by cell death that was partially mediated by Fas and involved loss of mitochondria l membrane potential, processing of procaspase-9 and -3, and activation of caspase-3. Addition of IL-12 prevented activation-induced cell death and pr omoted late proliferation. ICAM-1 + IL-12-costimulated Th cells were resist ant to Fas-mediated cell death through a mechanism that did not appear to i nvolve a decrease in either Fas or Fas ligand expression. IL-12 did not inh ibit the loss of mitochondrial membrane potential induced by ICAM-1-mediate d costimulation, and this finding was consistent with the inability of IFL- 12 to increase expression of the antiapoptotic Bcl-2 family members, Bcl-2 and Bcl-x(L). Interestingly, IL-12 promoted an altered processing of procas pase-9 and -3 and a decrease in the percentage of cells displaying caspase- 3 catalytic function. In conclusion, we now describe a novel regulatory fun ction for IL-12 in preventing Th cell death and, as a result, in greatly in creasing Th cell viability and expansion. Together, our findings indicate t hat IL-12 may perform this regulatory role by preventing Fas-mediated activ ation-induced cell death through inhibition of caspase-3 enzyme activity.