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Institute for Immunology, University Heidelberg, Heidelberg, Germany
Engagement of NTB-A on human NK cells by homophilic interaction with NTB-A-expressing target cells can trigger NK cell cytotoxicity, cytokine production, and proliferation. To better understand how NTB-A can activate NK cells, we analyzed the molecular mechanisms of NTB-A signaling. We show that NTB-A is tyrosine phosphorylated in unstimulated human NK cells and associates with SLAM-associated protein (SAP) and EAT-2. This phosphorylation of NTB-A is mediated by Src family kinases and is most likely a result of the homophilic interaction of NTB-A among neighboring NK cells. Stimulation of NK cells by NTB-A-positive targets results in increased NTB-A phosphorylation. The cytoplasmic tail of NTB-A contains three tyrosines, two of which are embedded within an immunoreceptor tyrosine-based switch motif. We generated a NTB-A-negative NK cell line, in which we expressed different mutants of NTB-A. Functional studies showed that the second tyrosine is sufficient and essential for NTB-A-mediated cytotoxicity. EAT-2, but not SAP, is recruited to this second tyrosine, indicating that SAP may be dispensable for this NTB-A function. To further investigate this, we silenced SAP expression in NK cell lines. Functional analysis of these cells showed that NTB-A can mediate NK cell cytotoxicity in the absence of SAP, probably via EAT-2. In contrast, NTB-A-mediated IFN-
production was greatly reduced in the absence of SAP, demonstrating that cytokine production and cytotoxicity are differentially dependent on SAP and possibly EAT-2.
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 the Deutsche Forschungsgemeinschaft (SFB 405, A9).
2 Current address: Division of Cell and Molecular Biology, Imperial College London, London, U.K.
3 Address correspondence and reprint requests to Dr. Carsten Watzl, Institute for Immunology, University Heidelberg, INF 305, 69120 Heidelberg, Germany. E-mail address: carsten.watzl{at}urz.uni-heidelberg.de
4 Abbreviations used in this paper: SLAM, signaling lymphocytic activation molecule; ITSM, immunoreceptor tyrosine-based switch motif; PLC, phospholipase C; SAP, SLAM-associated protein; SH, Src homology; SHP, SH region 2 domain-containing phosphatase; shRNA, short hairpin RNA; SRR, SLAM-related receptor; XLP, X-linked lymphoproliferative syndrome.
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