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Production in Activated Murine NK Cells1
* Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143; and
Amgen, Inc., Thousand Oaks, CA 91320
The functions of NK cells are regulated by the balance of
activating and inhibitory signals. The inhibitory NK cell receptors are
well understood; however, less is known about the activating signaling
pathways. To explore whether a costimulatory receptor, inducible
costimulator (ICOS), is involved in NK cell function, we assessed the
role of ICOS in NK cell-mediated cytotoxicity and cytokine production.
In addition, to determine whether ICOS contributes to the elimination
of tumors in vivo, we examined the tumor growth survival of mice
injected with a tumor expressing the ICOS ligand, B7RP-1. We found that
ICOS was up-regulated by cytokine stimulation in murine NK cells.
Consistent with ICOS expression on activated NK cells, ICOS-dependent
cytotoxicity and IFN-
production were observed, and appeared to
require signaling through the phosphoinositide 3-kinase pathway.
Interestingly, ICOS-mediated stimulation allowed activated NK cells to
kill more efficiently tumor cells expressing MHC class I. Furthermore,
fewer metastases appeared in the liver and spleen of mice injected with
the ICOS ligand-expressing tumor compared with mice bearing the
parental tumor. These results indicate that NK cell functions are
regulated by ICOS.
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