REQUIREMENT FOR STAT4 IN INTERLEUKIN-12-MEDIATED RESPONSES OF NATURAL-KILLER AND T-CELLS

SIGNAL transducers and activators of transcription (STATs) are activat ed by tyrosine phosphorylation in response to cytokines and mediate ma ny of their functional responses(1-3). Statil was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expresse d, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6, 7). IL-12 is required for the T-cell-independent induction of the cytokine interferon (IFN)-gamma, a keg step in the initial suppression of bacterial and parasitic infect ions. IL-12 is also important for the development of a Th1 response, w hich is critical for effective host defence against intracellular path ogens(8,9). To determine the function of Stat4 and its role in IL-12 s ignalling, we have produced mice that lack Stat4 by gene targeting. Th e mice were viable and fertile, with no detectable defects in haematop oiesis, However, all IL-12 functions tested were disrupted, including the induction of IFN-gamma, mitogenesis, enhancement of natural killer cytolytic function and Th1 differentiation.