title: NKG2D ligation relieves 2B4-mediated NK-cell self-tolerance in mice.
abstract: Along with MHC class I (MHCI), 2B4 provides nonredundant NK-cell inhibition in mice. The immunoregulatory role of 2B4 has been increasingly appreciated in models of tumor and viral infection, however, the interactions among 2B4, MHCI, and other activating NK-cell receptors remain uncertain. Here, we dissect the influence of two distinct inhibitory pathways in modulating NK-cell-mediated control of tumors expressing strong activating ligands, including RAE-1γ. In vitro cytotoxicity and in vivo peritoneal clearance assays using MHCI(+) CD48(+) (RMA-neo), MHCI(+) CD48(+) RAE-1γ (RMA-RAE-1γ), MHCI(-) CD48(+) (RMA-S-neo), and MHCI(-) CD48(+) RAE-1γ (RMA-S-RAE-1γ) tumor lines demonstrated that NKG2D activation supersedes the inhibitory effect of both 2B4- and MHCI-mediated immune-tolerance systems. Furthermore, 2B4KO mice subcutaneously challenged with RMA-neo and RMA-S-neo exhibited reduced tumor growth and significantly prolonged survival compared with WT mice, implying that 2B4 is constitutively engaged in the NK-cell tolerance mechanism in vivo. Nevertheless, the inhibitory effect of 2B4 is significantly attenuated when NK cells encountered highly stressed tumor cells expressing RAE-1γ, resulting in an immune response shift toward NK-cell activation and tumor regression. Therefore, our data highlight the importance of the 2B4-mediated inhibitory system as an alternate self-tolerance mechanism, whose role can be modulated by the strength of activating receptor signaling within the tumor microenvironment.
authors.affiliation: Global Research Laboratory, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Seon Ah
authors.initials: SA
authors.lastname: Lim
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Kim
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Kim
authors.forename: Joanne
authors.initials: J
authors.lastname: Ng
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: In Jung
authors.initials: IJ
authors.lastname: Jang
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: June-Chul
authors.initials: JC
authors.lastname: Lee
authors.forename: Cassian
authors.initials: C
authors.lastname: Yee
authors.forename: Vinay
authors.initials: V
authors.lastname: Kumar
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Lee
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D007152:Immunologic Capping / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance; D000071176:Signaling Lymphocytic Activation Molecule Family; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; C490007:Cd244a protein, mouse; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: 2B4; NKG2D; Natural killer cells; self-tolerance