Home LiteratureArticle Details
PMID: 18425106 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Up on the tightrope: natural killer cell activation and inhibition.

Nature immunology ·Vol. 9 ·No. 5 ·2008-05-00 ·Pages 495-502

Lanier LL

Abstract

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell-driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system.

MeSH Terms
Amino Acid Motifs/immunology Animals Antigens, CD/immunology Humans Killer Cells, Natural/immunology Lymphocyte Activation Membrane Proteins/immunology,metabolism NK Cell Lectin-Like Receptor Subfamily K Receptors, Immunologic/antagonists & inhibitors,chemistry,immunology,metabolism Receptors, Natural Killer Cell Signal Transduction/immunology Tyrosine
Chemicals
Antigens, CD HCST protein, human Hcst protein, mouse KLRK1 protein, human Klrk1 protein, mouse Membrane Proteins NK Cell Lectin-Like Receptor Subfamily K Receptors, Immunologic Receptors, Natural Killer Cell Tyrosine
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Lanier Lewis L
Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, California 94143-0414, USA. [email protected]
References (78)
78 references, click to expand
  1. 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells.
    J Exp Med. 2004 May 3;199(9):1245-54 PMID: 15123744
  2. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D.
    Nat Immunol. 2002 Dec;3(12):1142-9 PMID: 12426565
  3. Association between SAP and FynT: Inducible SH3 domain-mediated interaction controlled by engagement of the SLAM receptor.
    Mol Cell Biol. 2006 Aug;26(15):5559-68 PMID: 16847311
  4. 2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways.
    J Immunol. 2001 Dec 1;167(11):6210-6 PMID: 11714782
  5. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells.
    Nat Immunol. 2006 May;7(5):524-32 PMID: 16582911
  6. Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells.
    J Immunol. 2005 Feb 15;174(4):1922-31 PMID: 15699119
  7. An activating immunoreceptor complex formed by NKG2D and DAP10.
    Science. 1999 Jul 30;285(5428):730-2 PMID: 10426994
  8. A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells.
    J Exp Med. 2005 May 2;201(9):1421-33 PMID: 15867094
  9. Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase.
    J Biol Chem. 2002 Apr 12;277(15):13331-7 PMID: 11815622
  10. Analysis of Fc gamma RIII (CD16) membrane expression and association with CD3 zeta and Fc epsilon RI-gamma by site-directed mutation.
    J Immunol. 1991 Mar 1;146(5):1571-6 PMID: 1825220
  11. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway.
    Nat Immunol. 2003 Jun;4(6):557-64 PMID: 12740575
  12. Dysregulation of signaling pathways in CD45-deficient NK cells leads to differentially regulated cytotoxicity and cytokine production.
    Proc Natl Acad Sci U S A. 2006 May 2;103(18):7012-7 PMID: 16627620
  13. Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse.
    Mol Cell Biol. 2007 Dec;27(24):8583-99 PMID: 17923698
  14. Analysis of the molecular mechanism involved in 2B4-mediated NK cell activation: evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells.
    Eur J Immunol. 2000 Dec;30(12):3718-22 PMID: 11169415
  15. NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway.
    Nat Immunol. 2007 Dec;8(12):1345-52 PMID: 17952078
  16. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells.
    J Exp Med. 1991 Apr 1;173(4):1017-20 PMID: 2007850
  17. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.
    J Immunol. 2000 Sep 15;165(6):2932-6 PMID: 10975798
  18. Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor.
    Nat Immunol. 2005 Oct;6(10):1002-10 PMID: 16127454
  19. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.
    Proc Natl Acad Sci U S A. 2005 May 24;102(21):7641-6 PMID: 15894612
  20. The adaptor protein 3BP2 binds human CD244 and links this receptor to Vav signaling, ERK activation, and NK cell killing.
    J Immunol. 2005 Oct 1;175(7):4226-35 PMID: 16177062
  21. Identification and characterization of two related murine genes, Eat2a and Eat2b, encoding single SH2-domain adapters.
    Immunogenetics. 2006 Feb;58(1):15-25 PMID: 16425036
  22. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors.
    Immunity. 2005 Apr;22(4):427-38 PMID: 15845448
  23. Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity.
    Eur J Immunol. 2000 Nov;30(11):3309-18 PMID: 11093147
  24. The Vav-Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell-mediated killing.
    J Exp Med. 1998 Aug 3;188(3):549-59 PMID: 9687532
  25. NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease.
    J Exp Med. 2001 Aug 6;194(3):235-46 PMID: 11489943
  26. NK cell regulation by SLAM family receptors and SAP-related adapters.
    Immunol Rev. 2006 Dec;214:22-34 PMID: 17100873
  27. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion.
    Blood. 2006 Jan 1;107(1):159-66 PMID: 16150947
  28. Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3870-5 PMID: 10097130
  29. Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics.
    J Immunol. 2006 Aug 15;177(4):2349-55 PMID: 16887996
  30. DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase.
    J Biol Chem. 1998 Dec 4;273(49):32934-42 PMID: 9830044
  31. A Structural basis for the association of DAP12 with mouse, but not human, NKG2D.
    J Immunol. 2004 Aug 15;173(4):2470-8 PMID: 15294961
  32. The role of the NKG2D immunoreceptor in immune cell activation and natural killing.
    Immunity. 2002 Jul;17(1):19-29 PMID: 12150888
  33. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244).
    Blood. 2005 Jun 15;105(12):4722-9 PMID: 15713798
  34. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells.
    Nature. 1989 Dec 14;342(6251):803-5 PMID: 2532305
  35. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases.
    Nat Immunol. 2003 Jun;4(6):565-72 PMID: 12740576
  36. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes.
    J Exp Med. 1993 Oct 1;178(4):1397-406 PMID: 8376943
  37. Consequence of the SLAM-SAP signaling pathway in innate-like and conventional lymphocytes.
    Immunity. 2007 Nov;27(5):698-710 PMID: 18031694
  38. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.
    J Exp Med. 2000 Aug 7;192(3):337-46 PMID: 10934222
  39. KLRG1 binds cadherins and preferentially associates with SHIP-1.
    Int Immunol. 2007 Apr;19(4):391-400 PMID: 17307799
  40. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation.
    Nat Immunol. 2002 Dec;3(12):1150-5 PMID: 12426564
  41. SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells.
    Blood. 2002 Dec 15;100(13):4581-9 PMID: 12393695
  42. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.
    Nature. 1986 Feb 20-26;319(6055):675-8 PMID: 3951539
  43. ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells.
    Eur J Immunol. 2001 May;31(5):1428-37 PMID: 11465099
  44. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.
    J Immunol. 2002 Jan 15;168(2):671-9 PMID: 11777960
  45. Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family.
    J Immunol. 2001 Nov 15;167(10):5517-21 PMID: 11698418
  46. Immune inhibitory receptors.
    Science. 2000 Oct 6;290(5489):84-9 PMID: 11021804
  47. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
    Science. 1999 Jul 30;285(5428):727-9 PMID: 10426993
  48. Serial killing of tumor cells by human natural killer cells--enhancement by therapeutic antibodies.
    PLoS One. 2007 Mar 28;2(3):e326 PMID: 17389917
  49. Molecular dissection of 2B4 signaling: implications for signal transduction by SLAM-related receptors.
    Mol Cell Biol. 2004 Jun;24(12):5144-56 PMID: 15169881
  50. Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors.
    J Immunol. 2005 Jul 15;175(2):749-54 PMID: 16002670
  51. 2B4 is constitutively associated with linker for the activation of T cells in glycolipid-enriched microdomains: properties required for 2B4 lytic function.
    J Immunol. 2002 Jul 1;169(1):55-62 PMID: 12077228
  52. Cloning and characterization of the 2B4 gene encoding a molecule associated with non-MHC-restricted killing mediated by activated natural killer cells and T cells.
    J Immunol. 1993 Nov 15;151(10):5328-37 PMID: 8228228
  53. Cutting edge: dominance by an MHC-independent inhibitory receptor compromises NK killing of complex targets.
    J Immunol. 2006 Jun 15;176(12):7165-9 PMID: 16751359
  54. Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease.
    J Immunol. 2005 Apr 15;174(8):4551-8 PMID: 15814676
  55. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells.
    Blood. 2004 Apr 15;103(8):3065-72 PMID: 15070686
  56. Inappropriate recruitment and activity by the Src homology region 2 domain-containing phosphatase 1 (SHP1) is responsible for receptor dominance in the SHIP-deficient NK cell.
    J Immunol. 2007 Dec 15;179(12):8009-15 PMID: 18056340
  57. A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells.
    J Immunol. 1993 Jul 1;151(1):60-70 PMID: 8326140
  58. Fc gamma receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells.
    J Exp Med. 1992 Dec 1;176(6):1751-5 PMID: 1281218
  59. 2B4 inhibits NK-cell fratricide.
    Blood. 2007 Sep 15;110(6):2020-3 PMID: 17537992
  60. Direct and indirect interactions of the cytoplasmic region of CD244 (2B4) in mice and humans with FYN kinase.
    J Biol Chem. 2007 Aug 31;282(35):25385-94 PMID: 17599905
  61. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases.
    Nat Immunol. 2002 Mar;3(3):288-94 PMID: 11836527
  62. Regulation of Ly49D/DAP12 signal transduction by Src-family kinases and CD45.
    J Immunol. 2006 Jun 1;176(11):6615-23 PMID: 16709819
  63. 2B4-mediated activation of human natural killer cells.
    Mol Immunol. 2000 Jun;37(9):493-501 PMID: 11163399
  64. Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity.
    J Exp Med. 2004 Sep 20;200(6):817-23 PMID: 15365099
  65. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.
    J Immunol. 1999 Jun 15;162(12):6981-5 PMID: 10358138
  66. Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells.
    J Immunol. 2005 Jan 15;174(2):800-7 PMID: 15634901
  67. Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9611-6 PMID: 11493682
  68. Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions.
    Blood. 2006 Apr 15;107(8):3181-8 PMID: 15905190
  69. Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn.
    J Exp Med. 2005 Jul 4;202(1):181-92 PMID: 15998796
  70. Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts.
    J Exp Med. 2003 Jan 6;197(1):77-85 PMID: 12515815
  71. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules.
    Annu Rev Immunol. 2007;25:337-79 PMID: 17201683
  72. Multiplicity and plasticity of natural killer cell signaling pathways.
    Blood. 2006 Mar 15;107(6):2364-72 PMID: 16291591
  73. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
    Immunity. 2004 Sep;21(3):357-66 PMID: 15357947
  74. Protein kinase C regulates expression and function of inhibitory killer cell Ig-like receptors in NK cells.
    J Immunol. 2007 Oct 15;179(8):5281-90 PMID: 17911614
  75. Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity.
    Mol Cell Biol. 2003 Sep;23(17):6291-9 PMID: 12917349
  76. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors.
    Eur J Immunol. 2004 Apr;34(4):961-71 PMID: 15048706
  77. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells.
    J Exp Med. 2000 Oct 2;192(7):1059-68 PMID: 11015446
  78. NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244).
    J Immunol. 2000 Oct 1;165(7):3545-8 PMID: 11034353
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni1581
Email
[email protected]
Published
2008-05-00
Pages
495-502
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2669298
Subset
IM
Grants
NCI NIH HHS · U01 CA105379 · United States
NIAID NIH HHS · P01 AI064520-040002 · United States
NIAID NIH HHS · AI066897 · United States
NCI NIH HHS · CA095137 · United States
NIAID NIH HHS · AI64520 · United States
NCI NIH HHS · R01 CA095137-05 · United States
NIAID NIH HHS · R01 AI068129 · United States
NIAID NIH HHS · R37 AI066897 · United States
NIAID NIH HHS · R37 AI066897-08 · United States
NIAID NIH HHS · R01 AI068129-08 · United States
NCI NIH HHS · CA105379 · United States
NCI NIH HHS · R01 CA095137 · United States
NIAID NIH HHS · AI068129 · United States
NIAID NIH HHS · P01 AI064520 · United States
External Links
PubMed source DOI: 10.1038/ni1581 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2