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Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115
IL-2 exerts potent but distinct functional effects on two critical
cell populations of the immune system, T cells and NK cells. Whereas
IL-2 leads to proliferation in both cell types, it enhances
cytotoxicity primarily in NK 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 mechanism 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 lines, in addition
to the activation of STAT1 and STAT5, IL-2 induces tyrosine
phosphorylation of STAT4, a STAT previously reported to be activated
only in response to IL-12 and IFN-
. This activation of STAT4 in
response to IL-2 is not due to the autocrine production of IL-12 or
IFN-. STAT4 activated 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 through 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 occurs in primary resting and
activated NK cells, it does not occur in primary resting T cells or
mitogen-activated T cells. The unique activation of the STAT4-signaling
pathway in NK cells may underlie the distinct functional effect of IL-2
on this cell population.
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