The extracellular signal-regulated kinase pathway is required for activation-induced cell death of T cells

T cells can undergo activation-induced cell death (AICD) upon stimulation o f the T cell receptor-CD3 complex. We found that the extracellular signal-r egulated kinase (ERK) pathway is activated during AICD, Transient transfect ion of a dominant interfering mutant of mitogen-activated/extracellular sig nal-regulated receptor protein kinase kinase (MEK1) demonstrated that down- regulation of the ERK pathway inhibited Fast expression during AICD, wherea s activation of the ERK pathway with a constitutively active MEK1 resulted in increased expression of Fast. We also found that pretreatment with the s pecific MEK1 inhibitor PD98059 prevented the induction of Fast expression d uring AICD and inhibited AICD. However, PD98059 had no effect on other apop totic stimuli. We found only very weak ERK activity during Fas-mediated apo ptosis (induced by Fas cross-linking). Furthermore, preincubation with the MEK1 inhibitor did not inhibit Fas-mediated apoptosis, Finally, we also dem onstrated that pretreatment with the MEK1 inhibitor could delay and decreas e the expression of the orphan nuclear steroid receptor Nur77, which has be en shown to be essential for AICD. In conclusion, this study demonstrates t hat the ERK pathway is required for AICD of T cells and appears to regulate the induction of Nur77 and Fast expression during AICD.