IL-2 exerts potent but distinct functional effects on two critical cell pop
ulations of the immune system, T cells and NK cells. Whereas IL-2 leads to
proliferation in both cell types, it enhances cytotoxicity primarily in NR
cells. In both T cells and NK cells, IL-2 induces the activation of STAT1,
STAT3, and STAT5. Given this similarity in intracellular signaling, the mec
hanism underlying the distinct response to IL-2 in T cells and NK cells is
not clear. In this study, we show that in primary NK cells and NK cell line
s, in addition to the activation of STAT1 and STAT5, IL-2 induces tyrosine
phosphorylation of STAT4, a STAT previously reported to be activated only i
n response to IL-12 and IFN-alpha. This activation of STAT4 in response to
IL-2 is not due to the autocrine production of IL-12 or IFN-alpha. STAT4 ac
tivated in response to IL-2 is able to bind to a STAT-binding DNA sequence,
suggesting that in NK cells IL-2 is capable of activating target genes thr
ough phosphorylation of STAT4. IL-2 induces the activation of Jak2 uniquely
in NK cells, which may underlie the ability of IL-2 to activate STAT4 only
in these cells. Although the activation of STAT4 in response to IL-2 occur
s in primary resting and activated NK cells, it does not occur in primary r
esting T cells or mitogen-activated T cells. The unique activation of the S
TAT4-signaling pathway in NK cells may underlie the distinct functional eff
ect of IL-2 on this cell population.