title: 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells.
abstract: Natural killer (NK) cells are critical in the immune response to tumor cells, virally infected cells, and bone marrow allografts. 2B4 (CD244) is expressed on all NK cells and the ligand for 2B4, CD48, is expressed on hematopoietic cells. Cross-linking 2B4 on NK cells with anti-2B4 monoclonal antibody leads to NK cell activation in vitro. Therefore, 2B4 is considered to be an activating receptor. Surprisingly, we have found, using antibody-blocking and 2B4-deficient NK cells, that NK lysis of CD48(+) tumor and allogeneic targets is inhibited by 2B4 ligation. Interferon gamma production by NK cells is also inhibited. Using a peritoneal tumor clearance assay, it was found that 2B4(-/-) mice have increased clearance of CD48(+) tumor cells in vivo. Retroviral transduction of 2B4 was sufficient to restore inhibition in 2B4(-/-) primary NK cells. It was found that although mature NK cells express SH2D1A, in vitro-derived NK cells do not. However, both populations are inhibited by 2B4 ligation. This indicates that 2B4 inhibitory signaling occurs regardless of the presence of SH2D1A. These findings reveal a novel role for 2B4 as a non-major histocompatibility complex binding negative regulator of NK cells.
authors.affiliation: Department of Biochemistry, Korea University College of Medicine, Sungbuk-Gu, Anam-Dong, Seoul 136-705, Korea. kyunglee@korea.ac.kr
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Lee
authors.forename: Megan E
authors.initials: ME
authors.lastname: McNerney
authors.forename: Susan E
authors.initials: SE
authors.lastname: Stepp
authors.forename: Porunelloor A
authors.initials: PA
authors.lastname: Mathew
authors.forename: John D
authors.initials: JD
authors.lastname: Schatzle
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.forename: Vinay
authors.initials: V
authors.lastname: Kumar
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000071178:CD48 Antigen; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D015703:Antigens, CD; D000071178:CD48 Antigen; C490007:Cd244a protein, mouse; C000604066:Cd48 protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family