Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function

This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated...

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Bibliographic Details
Published in:Journal of Immunology 2007-06, Vol.178 (12), p.7540-7549
Main Authors: Swann, Jeremy B, Hayakawa, Yoshihiro, Zerafa, Nadeen, Sheehan, Kathleen C. F, Scott, Bernadette, Schreiber, Robert D, Hertzog, Paul, Smyth, Mark J
Format: Article
Language:English
Subjects:
Animals
Antibodies - pharmacology
Cytokines - therapeutic use
Homeostasis
Immunotherapy
Interferon Type I - physiology
Interferon Type I - therapeutic use
Killer Cells, Natural - drug effects
Killer Cells, Natural - immunology
Lymphocyte Activation
Mice
Mice, Mutant Strains
Neoplasms - immunology
Neoplasms - prevention & control
Neoplasms - therapy
Receptor, Interferon alpha-beta - antagonists & inhibitors
Receptor, Interferon alpha-beta - chemistry
Receptor, Interferon alpha-beta - genetics
Xenograft Model Antitumor Assays
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Summary:This study demonstrates that type I IFNs are an early and critical regulator of NK cell numbers, activation, and antitumor activity. Using both IFNAR1- and IFNAR2-deficient mice, as well as an IFNAR1-blocking Ab, we demonstrate that endogenous type I IFN is critical for controlling NK cell-mediated antitumor responses in many experimental tumor models, including protection from methylcholanthrene-induced sarcomas, resistance to the NK cell-sensitive RMA-S tumor and cytokine immunotherapy of lung metastases. Protection from RMA-S afforded by endogenous type I IFN is more potent than that of other effector molecules such as IFN-gamma, IL-12, IL-18, and perforin. Furthermore, cytokine immunotherapy using IL-12, IL-18, or IL-21 was effective in the absence of endogenous type I IFN, however the antimetastatic activity of IL-2 was abrogated in IFNAR-deficient mice, primarily due to a defect in IL-2-induced cytotoxic activity. This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.178.12.7540