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Laboratory of Experimental Immunology, National Cancer Institute, Frederick, MD 21701
In an attempt to understand potential novel functions of receptors
in vivo, we evaluated gene expression after cross-linking the
activating Ly-49D mouse NK receptor. Gene expression was evaluated
using a mouse GEM 2 microarray chip (Incyte Genomics, St. Louis,
MO). Each chip displays a total of 8734 elements. The strongly
induced genes fell into two categories: 1) soluble factors and 2)
apoptotic genes. The majority of the strongly induced mRNAs as analyzed
by microarray hybridization were chemokine genes. RNase protection
assays and chemokine protein production analysis validated the
microarray results, as cross-linking the Ly-49D mouse NK receptor
induced high levels of IFN-
, lymphotactin, macrophage-inflammatory
protein (MIP)1
, and MIP1
. This gene expression was
specific because other chemokines were not induced by anti-Ly-49D
receptors. In addition, a series of pharmacological inhibitors were
used to identify the key signaling pathways involved in the cellular
response. The primary Ly-49D signaling for IFN- production is
predominately mediated through Src kinase pathways involving membrane
proximal events, whereas MIP1 and MIP1 gene induction is more
complex and may involve multiple biochemical pathways. Thus, we
conclude that a primary role for the activating NK receptors in vivo
may be to trigger soluble factor production and regulation of the
immune response. This would place NK cells and their activating Ly-49
receptors as important initiators of microbial immunity and key
elements of the innate immune system.
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