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Production and Antibody-Dependent Cellular Cytotoxicity in Human NK Cells1
,
,¶,¶
* Department of Molecular Virology, Immunology, and Medical Genetics,
The Center for Biostatistics,
The Division of Hematology/Oncology, Department of Internal Medicine,
The Department of Medical Chemistry, College of Pharmacy, and
¶ The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
TGF-β can be a potent suppressor of lymphocyte effector cell functions and can mediate these effects via distinct molecular pathways. The role of TGF-β in regulating CD16-mediated NK cell IFN-
production and antibody-dependent cellular cytotoxicity (ADCC) is unclear, as are the signaling pathways that may be utilized. Treatment of primary human NK cells with TGF-β inhibited IFN- production induced by CD16 activation with or without IL-12 or IL-2, and it did so without affecting the phosphorylation/activation of MAP kinases ERK and p38, as well as STAT4. TGF-β treatment induced SMAD3 phosphorylation, and ectopic overexpression of SMAD3 resulted in a significant decrease in IFN- gene expression following CD16 activation with or without IL-12 or IL-2. Likewise, NK cells obtained from smad3–/– mice produced more IFN- in response to CD16 activation plus IL-12 when compared with NK cells obtained from wild-type mice. Coactivation of human NK cells via CD16 and IL-12 induced expression of T-BET, the positive regulator of IFN-, and T-BET was suppressed by TGF-β and by SMAD3 overexpression. An extended treatment of primary NK cells with TGF-β was required to inhibit ADCC, and it did so by inhibiting granzyme A and granzyme B expression. This effect was accentuated in cells overexpressing SMAD3. Collectively, our results indicate that TGF-β inhibits CD16-mediated human NK cell IFN- production and ADCC, and these effects are mediated via SMAD3.
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 by National Cancer Institute Grants CA16058 (M.A.C.), CA95426 (M.A.C.), CA68458 (M.A.C.), and CA095512 (D.P.) and the D. Warren Brown Foundation (J.C.B.). D.P. is a Scholar of the Leukemia and Lymphoma Society.
2 Address correspondence and reprint requests to Drs. Rossana Trotta and Michael A. Caligiuri, The Ohio State University Comprehensive Cancer Center, 884 OSU Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. E-mail addresses: rossana.trotta{at}osumc.edu and michael.caligiuri{at}osumc.edu
3 Abbreviations used in this paper: PLC, phospholipase C; ADCC, antibody-dependent cellular cytotoxicity; hIgG, human IgG; wt, wild type.
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