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PMID: 15123744 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells.

The Journal of experimental medicine ·Vol. 199 ·No. 9 ·2004-05-03 ·Pages 1245-54

Lee KM, McNerney ME, Stepp SE, Mathew PA, Schatzle JD, Bennett M, Kumar V

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.

MeSH Terms
Animals Antigens, CD/genetics,immunology CD48 Antigen Cytotoxicity, Immunologic/immunology Killer Cells, Natural/immunology Major Histocompatibility Complex Membrane Glycoproteins/deficiency,genetics,immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, SCID Receptors, Immunologic/deficiency,genetics,immunology Signaling Lymphocytic Activation Molecule Family
Chemicals
Antigens, CD CD48 Antigen Cd244a protein, mouse Cd48 protein, mouse Membrane Glycoproteins Receptors, Immunologic Signaling Lymphocytic Activation Molecule Family
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lee Kyung-Mi
Department of Biochemistry, Korea University College of Medicine, Sungbuk-Gu, Anam-Dong, Seoul 136-705, Korea. [email protected]
McNerney Megan E
Stepp Susan E
Mathew Porunelloor A
Schatzle John D
Bennett Michael
Kumar Vinay
References (57)
57 references, click to expand
  1. Cutting edge: induction of IFN-gamma production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells.
    J Immunol. 2001 Aug 15;167(4):1877-81 PMID: 11489965
  2. Identification of the 2B4 molecule as a counter-receptor for CD48.
    J Immunol. 1998 Dec 1;161(11):5809-12 PMID: 9834056
  3. 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
  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. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells.
    J Exp Med. 2002 Feb 4;195(3):335-41 PMID: 11828008
  6. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48.
    J Exp Med. 1998 Dec 7;188(11):2083-90 PMID: 9841922
  7. 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
  8. Activating interactions in human NK cell recognition: the role of 2B4-CD48.
    Eur J Immunol. 1999 May;29(5):1676-83 PMID: 10359122
  9. Natural killer cells in antiviral defense: function and regulation by innate cytokines.
    Annu Rev Immunol. 1999;17:189-220 PMID: 10358757
  10. 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
  11. Tolerance and alloreactivity of the Ly49D subset of murine NK cells.
    J Immunol. 1999 Aug 15;163(4):1859-67 PMID: 10438920
  12. Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4.
    Tissue Antigens. 1999 Jul;54(1):27-34 PMID: 10458320
  13. Gene structure of the murine NK cell receptor 2B4: presence of two alternatively spliced isoforms with distinct cytoplasmic domains.
    Eur J Immunol. 1999 Aug;29(8):2392-9 PMID: 10458751
  14. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells.
    J Exp Med. 2002 Feb 4;195(3):343-51 PMID: 11828009
  15. 2B4 functions as a co-receptor in human NK cell activation.
    Eur J Immunol. 2000 Mar;30(3):787-93 PMID: 10741393
  16. Plat-E: an efficient and stable system for transient packaging of retroviruses.
    Gene Ther. 2000 Jun;7(12):1063-6 PMID: 10871756
  17. 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
  18. 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
  19. Defective NK cell activation in X-linked lymphoproliferative disease.
    J Immunol. 2000 Oct 1;165(7):3549-53 PMID: 11034354
  20. 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
  21. Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4.
    Int Immunol. 2000 Dec;12(12):1749-57 PMID: 11099315
  22. 2B4-mediated activation of human natural killer cells.
    Mol Immunol. 2000 Jun;37(9):493-501 PMID: 11163399
  23. On guard--activating NK cell receptors.
    Nat Immunol. 2001 Jan;2(1):23-7 PMID: 11135574
  24. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages.
    Nat Immunol. 2000 Aug;1(2):119-26 PMID: 11248803
  25. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.
    Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7449-54 PMID: 11404475
  26. Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product.
    Nat Immunol. 2001 Aug;2(8):681-90 PMID: 11477403
  27. Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells.
    Blood. 2002 Mar 1;99(5):1723-9 PMID: 11861289
  28. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4526-31 PMID: 11917118
  29. NK cells, MHC class I molecules and the missing self.
    Scand J Immunol. 2002 Mar;55(3):221-8 PMID: 11940227
  30. KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential.
    J Immunol. 2002 Jun 15;168(12):6208-14 PMID: 12055234
  31. Variable receptors controlling activation and inhibition of NK cells.
    Curr Opin Immunol. 2002 Oct;14(5):615-21 PMID: 12183162
  32. The dual-function CD150 receptor subfamily: the viral attraction.
    Nat Immunol. 2003 Jan;4(1):19-24 PMID: 12496974
  33. CD8-independent tumor cell recognition is a property of the T cell receptor and not the T cell.
    J Immunol. 2003 Mar 1;170(5):2582-9 PMID: 12594285
  34. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells.
    J Immunol. 2003 Apr 1;170(7):3572-6 PMID: 12646619
  35. Enhanced antitumor immunity in mice deficient in CD69.
    J Exp Med. 2003 May 5;197(9):1093-106 PMID: 12732655
  36. Cutting edge: the NK cell receptor 2B4 augments antigen-specific T cell cytotoxicity through CD48 ligation on neighboring T cells.
    J Immunol. 2003 May 15;170(10):4881-5 PMID: 12734329
  37. Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors.
    Nat Immunol. 2003 Aug;4(8):801-7 PMID: 12858173
  38. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease).
    Lancet. 1975 Apr 26;1(7913):935-40 PMID: 48119
  39. Hematopathology and Pathogenesis of the X-linked recessive lymphoproliferative syndrome.
    Am J Med. 1977 Feb;62(2):225-33 PMID: 835602
  40. Expression of CD1 and class I MHC antigens by human thymocytes.
    J Immunol. 1989 Apr 15;142(8):2714-20 PMID: 2467935
  41. Expression of the Blast-1 activation/adhesion molecule and its identification as CD48.
    J Immunol. 1991 Apr 1;146(7):2192-200 PMID: 1848579
  42. CD69-mediated pathway of lymphocyte activation: anti-CD69 monoclonal antibodies trigger the cytolytic activity of different lymphoid effector cells with the exception of cytolytic T lymphocytes expressing T cell receptor alpha/beta.
    J Exp Med. 1991 Dec 1;174(6):1393-8 PMID: 1720808
  43. 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
  44. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes.
    J Exp Med. 1993 Oct 1;178(4):1397-406 PMID: 8376943
  45. 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
  46. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment.
    J Exp Med. 1995 Apr 1;181(4):1445-58 PMID: 7699329
  47. 2B4, a new member of the immunoglobulin gene superfamily, is expressed on murine dendritic epidermal T cells and plays a functional role in their killing of skin tumors.
    J Invest Dermatol. 1995 Oct;105(4):592-6 PMID: 7561164
  48. The role of natural killer cells in transplantation.
    Curr Opin Immunol. 1995 Oct;7(5):626-31 PMID: 8573304
  49. Triggering of natural killer cells by the costimulatory molecule CD80 (B7-1)
    Immunity. 1996 Oct;5(4):311-7 PMID: 8885864
  50. Both human alpha/beta and gamma interferons upregulate the expression of CD48 cell surface molecules.
    J Interferon Cytokine Res. 1997 Jan;17(1):17-26 PMID: 9041467
  51. Generation of lytic natural killer 1.1+, Ly-49- cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates.
    J Exp Med. 1997 Nov 3;186(9):1609-14 PMID: 9348320
  52. The basis for self-tolerance of natural killer cells in beta2-microglobulin- and TAP-1- mice.
    J Immunol. 1997 Dec 1;159(11):5219-25 PMID: 9548460
  53. NK cell receptors.
    Annu Rev Immunol. 1998;16:359-93 PMID: 9597134
  54. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
    Nat Genet. 1998 Oct;20(2):129-35 PMID: 9771704
  55. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
    Nature. 1998 Oct 1;395(6701):462-9 PMID: 9774102
  56. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13765-70 PMID: 9811875
  57. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells.
    EMBO J. 2001 Nov 1;20(21):5840-52 PMID: 11689425
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031989
Email
[email protected]
Published
2004-05-03
Pages
1245-54
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211902
Subset
IM
Grants
NIAID NIH HHS · R01 AI020451 · United States
NIGMS NIH HHS · T32 GM007281 · United States
External Links
PubMed source DOI: 10.1084/jem.20031989 PMC Full Text View journal details
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