2003 Articles

Regulation of Lymphocyte Apoptosis by Interferon Regulatory Factor 4 (IRF-4)

Fanzo, Jessica C.; Hu, Chuan-Min; Jang, So Young; Pernis, Alessandra B.

To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fasmediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4–deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4–transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4–deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.