AN IRF-1-DEPENDENT PATHWAY OF DNA DAMAGE-INDUCED APOPTOSIS IN MITOGEN-ACTIVATED T-LYMPHOCYTES

LYMPHOCYTES are particularly susceptible to DNA damage-induced apoptos is, a response which may serve as a form of 'altruistic suicide' to co unter their intrinsic high potential for mutation and clonal expansion (1). The tumour suppressor p53 has been shown to regulate this type of apoptosis in thymocytes(2,3), but an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogen-activated matu re T lymphocytes(4). Here we show that DNA damage-induced apoptosis in these T lymphocytes is dependent on the antioncogenic transcription f actor interferon regulatory factor (IRF)-1 (refs 5-7). Thus two differ ent anti-oncogenic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. We also show that mi togen induction of the interleukin-1 beta converting enzyme (ICE) gene (8-10), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, is IRF-1-dependent. Ectopic overexpression of IRE-1 resul ts in the activation of the endogenous gene for ICE and enhances the s ensitivity of cells to radiation-induced apoptosis.