Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions.
2B4 belongs to the CD2 subset of the IgG family of receptors. Members in this family have been shown to function as coreceptors via homophilic or heterophilic interactions. Both 2B4 and CD2 bind to CD48, another member of this family. Because all 3 molecules are expressed on natural killer (NK) cells, it raises a possibility that the binding of 2B4 and CD2 to CD48 among NK cells may have functional consequences. Using specific monoclonal antibodies and gene-deficient NK cells, we found that 2B4/CD48, but not CD2/CD48, interaction is essential for IL-2-driven expansion and activation of murine NK cells. In the absence of 2B4/CD48 interaction, NK cytotoxicity and IFN-gamma secretion on tumor target exposure is severely impaired. Impaired activation of NK cells in 2B4-deficient mice was also demonstrated by poor NK-mediated clearance of syngeneic tumor cells in these mice. Functional impairment of NK cells in the absence of 2B4/CD48 interactions was accompanied by defective calcium signaling, suggesting that the early signaling pathway of NK receptors is inhibited. Finally, homotypic interactions among NK cells through 2B4/CD48 was visualized by specific localization of GFP-tagged 2B4 onto NK-NK conjugation sites. Thus, these data identify a novel mechanism whereby NK effector function is regulated via homotypic 2B4/CD48 interactions.
Lee
Kyung-Mi
KM
Department of Pathology, University of Chicago, IL, USA. kyunglee@korea.ac.kr
Forman
John P
JP
McNerney
Megan E
ME
Stepp
Susan
S
Kuppireddi
Sumalatha
S
Guzior
Dustin
D
Latchman
Yvette E
YE
Sayegh
Mohamed H
MH
Yagita
Hideo
H
Park
Chul-Kyu
CK
Oh
Seog Bae
SB
Wülfing
Christoph
C
Schatzle
John
J
Mathew
Porunelloor A
PA
Sharpe
Arlene H
AH
Kumar
Vinay
V
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D000071178:CD48 Antigen; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; C490007:Cd244a protein, mouse; C000604066:Cd48 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma