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2 and Phospholipase C1 in the Terminal Maturation of NK Cells1
,¶
* Blood Research Institute, Milwaukee, WI 53226;
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, People’s Republic of China;
Dali University, Dali, Yunnan, People’s Republic of China;
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and
¶ Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226
NK cells play a central role in mediating innate immune responses. Activation of NK cells results in cytotoxicity, cytokine, and chemokine secretions. In this study, we show that in mice with targeted deletion of phospholipase C
(PLC)2, one of the key signal transducers, there are profound effects on the development and terminal maturation of NK cells. Lack of PLC2 significantly impaired the ability of lineage-committed NK precursor cells to acquire subset-specific Ly49 receptors and thereby terminal maturation of NK cells. Overexpression of isozyme, PLC1, in PLC2-deficient NK cells resulted in the successful Ly49 acquisition and terminal maturation of the NK cells; however, it could only partially rescue NKG2D-mediated cytotoxicity with no cytokine production. Furthermore, PLC2-deficient NK cells failed to mediate antitumor cytotoxicity and inflammatory cytokine production, displaying a generalized hyporesponsiveness. Our results strongly demonstrate that PLC1 and PLC2 play nonredundant and obligatory roles in NK cell ontogeny and in its effector functions.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by American Cancer Society Grants RSG-02-172-01-LIB (to S.M.) and RSG CCG-106204 (to D.W.); Roche Organ Transplant Research Foundation Grant 111662730 (to S.M.); and National Institutes of Health Grants U19 AI062627-01, NO1-HHSN26600 500032C, and R01 A1064826 (to S.M.), R01 AI52327 (to R.W.), and R01 HL073284 (to D.W.). J.R. is a Northwestern Mutual Postdoctoral Fellow, from the Cancer Center of the Medical College of Wisconsin.
2 Address correspondence and reprint requests to Dr. Subramaniam Malarkannan or Dr. Demin Wang, Blood Research Institute, Milwaukee, WI 53226. E-mail addresses: subra.malar{at}bcw.edu or demin.wang{at}bcw.edu
3 Abbreviations used in this paper: H60, minor histocompatibility Ag 60; PTK, protein tyrosine kinase; PLC, phospholipase C; DAG, 1,2-diacylglycerol; PKC, protein kinase C; IP3. inositol 1,4,5-triphosphate; CLP, common lymphoid progenitor; BM, bone marrow; NKP, NK precursor; IRES, internal ribosome entry site; WT, wild type; EL4H60, EL4 stably transfected with H60.
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