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* University of Chicago, Department of Pathology, Chicago, IL 60637; and
Center for Advanced Research in Biotechnology, WM Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, MD 20850
2B4 belongs to the CD2 family of molecules and is expressed on all NK, 
, and memory CD8+ (
β) T cells. The murine NK receptor 2B4 exhibits both inhibitory and activating functions, whereas human 2B4 has been reported to be an activating molecule. How murine 2B4 can act both as an activating and inhibitory receptor and what distinguishes its function from human 2B4 have remained largely unknown. We use here a model system that allows the study of human and murine 2B4 under identical and controlled conditions. These studies reveal that both human and mouse 2B4 can activate or inhibit NK cells. We show here that the level of 2B4 expression and the degree of 2B4 cross-linking play a significant role in the regulation of signaling lymphocyte activation molecule-associated protein-mediated activation by 2B4. A high level of 2B4 expression, heavy cross-linking, and relative paucity of signaling lymphocyte activation molecule-associated protein promote inhibitory function. Our studies demonstrate how a single receptor can have opposing function depending on the degree of receptor expression, extent of its ligation, and the relative abundance of certain adaptor molecules. Because the levels of 2B4 and CD48 are dynamically regulated, these findings have implications for the regulation of NK cell function.
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 Institutes of Health training grants from Cardiovascular Biology and Biochemistry (Sept 2005-Aug 2006) and Committee on Immunology (Sept 2006-Aug 2007) (to L.K.C.). R.A.M. was supported by National Institutes of Health Grant AI047990.
2 Address correspondence and reprint requests to Dr. Lukasz K Chlewicki, Department of Pathology, University of Chicago, 5841 South Maryland Avenue, MC-3083 Room S-315, Chicago, IL 60637. E-mail address: lchlewicki{at}sciencetrader.com
3 Abbreviations used in this paper: ITSM, Immunotyrosine-based switch motif; XLP, X-linked lymphoproliferative disease; SAP, signaling lymphocyte activation molecule (SLAM)-associated protein; LAK, lymphokine-activated killer; DC, dendritic cell; MFU, mean fluorescence unit.
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  D. Yuan Comment on "Molecular Basis of the Dual Functions of 2B4 (CD244)" J. Immunol., October 15, 2008; 181(8): 5181 - 5181. [Full Text] [PDF]
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L. K. Chlewicki Response to Comment on "Molecular Basis of the Dual Functions of 2B4 (CD244)" J. Immunol., October 15, 2008; 181(8): 5181 - 5181. [Full Text] [PDF]
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