STAT4 was originally identified using degenerate primers complementary to sequences encoding conserved regions of other STAT proteins. The STAT4 protein is most similar to STAT1 (52%) and STAT3 (47%). Functionally, STAT4 is similar to other STAT family members in that it can be tyrosine phosphorylated by Jak1 or Jak2. STAT4 forms homodimers and heterodimers with related STAT family members. Tyrosine phosphorylated STAT4 can bind the IFN-gamma activated site (GAS). Serine phosphorylation of STAT is also required for maximal transcriptional activity. STAT4 expression is restricted to the thymus, spleen and testis. Until recently the cytokine(s) responsible for activation of STAT4 had not been identified. STAT4 is now known to be activated by the cytokine interleukin-12 (IL-12). IL-12 is required for the T-cell independent induction of IFN-gamma which is a key step in the initial suppression of bacterial and parasitic infections. In addition, IL-12 is required for the development of a Th1 response which is necessary for effective host defense against intracellular pathogens. Perhaps not surprisingly, STAT4-deficient mice display impaired IL-12 development of Th1 cells and enhanced development of Th2 cells. A recent study has suggested that tyrosine and serine phosphorylation of STAT4 can be induced by both IL-12 and IFN-alpha.