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Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation¹

Subramaniam Malarkannan^2,*,,, Jeyarani Regunathan^*, Haiyan Chu^*, Snjezana Kutlesa^*, Yuhong Chen, Hu Zeng, Renren Wen and Demin Wang^2,,

^* Laboratory of Molecular Immunology, Receptor Signaling Laboratory, Blood Research Institute, Department of Microbiology and Molecular Genetics, and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226

Activating receptors such as NKG2D and Ly49D mediate a multitude of effector functions including cytotoxicity and cytokine generation in NK cells. However, specific signaling events that are responsible for the divergence of distinct effector functions have yet to be determined. In this study, we show that lack of caspase recruitment domain-containing protein Bcl10 significantly affected receptor-mediated cytokine and chemokine generation, but not cytotoxicity against tumor cells representing "missing-self" or "induced-self." Lack of Bcl10 completely abrogated the generation of GM-CSF and chemokines and it significantly reduced the generation of IFN- (>75%) in NK cells. Commitment, development, and terminal maturation of NK cells were largely unaffected in the absence of Bcl10. Although IL-2-activated NK cells could mediate cytotoxicity to the full extent, the ability of the freshly isolated NK cells to mediate cytotoxicity was somewhat reduced. Therefore, we conclude that the Carma1-Bcl10-Malt1 signaling axis is critical for cytokine and chemokine generation, although it is dispensable for cytotoxic granule release depending on the activation state of NK cells. These results indicate that Bcl10 represents an exclusive "molecular switch" that links the upstream receptor-mediated signaling to cytokine and chemokine generations.

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 H.C. is the recipient of Breast Cancer Show House Postdoctoral Fellowship, from the Cancer Center of the Medical College of Wisconsin. This work was supported in part by American Cancer Society Scholar Grants RSG-02-172-LIB (to S.M.) and RSG CCG-106204 (to D.W.), Roche Organ Transplantation Research Foundation Grant 111662730 (to S.M.), and National Institutes of Health Grants R01 A1064826-01, U19 AI062627-01, NO1-HHSN26600500032C (to S.M.), R01 AI52327 (to R.W.), and R01 HL073284 (to D.W.).

² Address correspondence and reprint requests to Dr. Subramaniam Malarkannan, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226; E-mail address: subra.malar{at}bcw.edu or Dr. Demin Wang, Blood Research Institute, Milwaukee, WI 53226; E-mail address: demin.wang{at}bcw.edu

³ Abbreviations used in this paper: MHC I, MHC class I; PTK, protein tyrosine kinase; Malt, mucous-associated lymphoid tissue lymphoma; IKK, IB kinase; FO, follicular; MZ, marginal zone; WT, wild type; PKC, protein kinase C; BM, bone marrow; PLC, phospholipase C; 7-AAD, 7-aminoactinomycin D; DAG, 1,2-diacylglycerol.

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