2B4 Acts As a Non-major Histocompatibility Complex Binding Inhibitory Receptor on Mouse Natural Killer Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2004 May 5

PMID 15123744

Citations 80

Authors

Kyung-Mi Lee

Megan E McNerney

Susan E Stepp

Porunelloor A Mathew

John D Schatzle

Michael Bennett

Vinay Kumar

Affiliations

Soon will be listed here.

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.

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References

Rajagopalan S, Fu J, Long E . 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; 167(4):1877-81. DOI: 10.4049/jimmunol.167.4.1877. View

Latchman Y, McKay P, Reiser H . Identification of the 2B4 molecule as a counter-receptor for CD48. J Immunol. 1998; 161(11):5809-12. View

Bouchon A, Cella M, Grierson H, Cohen J, Colonna M . Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol. 2001; 167(10):5517-21. DOI: 10.4049/jimmunol.167.10.5517. View

Chuang S, Kumaresan P, Mathew P . 2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways. J Immunol. 2001; 167(11):6210-6. DOI: 10.4049/jimmunol.167.11.6210. View

Piccioli D, Sbrana S, Melandri E, Valiante N . Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med. 2002; 195(3):335-41. PMC: 2193592. DOI: 10.1084/jem.20010934. View

Brown M, Boles K, van der Merwe P, Kumar V, Mathew P, Barclay A . 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J Exp Med. 1998; 188(11):2083-90. PMC: 2212392. DOI: 10.1084/jem.188.11.2083. View

Schatzle J, Sheu S, Stepp S, Mathew P, Bennett M, Kumar V . Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4. Proc Natl Acad Sci U S A. 1999; 96(7):3870-5. PMC: 22387. DOI: 10.1073/pnas.96.7.3870. View

Nakajima H, Cella M, Langen H, Friedlein A, Colonna M . Activating interactions in human NK cell recognition: the role of 2B4-CD48. Eur J Immunol. 1999; 29(5):1676-83. DOI: 10.1002/(SICI)1521-4141(199905)29:05<1676::AID-IMMU1676>3.0.CO;2-Y. View

Biron C, Nguyen K, Pien G, Cousens L, Salazar-Mather T . Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol. 1999; 17:189-220. DOI: 10.1146/annurev.immunol.17.1.189. View

10.

Tangye S, Lazetic S, Woollatt E, Sutherland G, Lanier L, Phillips J . 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; 162(12):6981-5. View

11.

GEORGE T, Ortaldo J, Lemieux S, Kumar V, Bennett M . Tolerance and alloreactivity of the Ly49D subset of murine NK cells. J Immunol. 1999; 163(4):1859-67. View

12.

Boles K, Nakajima H, Colonna M, Chuang S, Stepp S, Bennett M . Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4. Tissue Antigens. 1999; 54(1):27-34. DOI: 10.1034/j.1399-0039.1999.540103.x. View

13.

Stepp S, Schatzle J, Bennett M, Kumar V, Mathew P . Gene structure of the murine NK cell receptor 2B4: presence of two alternatively spliced isoforms with distinct cytoplasmic domains. Eur J Immunol. 1999; 29(8):2392-9. DOI: 10.1002/(SICI)1521-4141(199908)29:08<2392::AID-IMMU2392>3.0.CO;2-R. View

14.

Ferlazzo G, Tsang M, Moretta L, Melioli G, Steinman R, Munz C . Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med. 2002; 195(3):343-51. PMC: 2193591. DOI: 10.1084/jem.20011149. View

15.

Sivori S, Parolini S, Falco M, Marcenaro E, Biassoni R, Bottino C . 2B4 functions as a co-receptor in human NK cell activation. Eur J Immunol. 2000; 30(3):787-93. DOI: 10.1002/1521-4141(200003)30:3<787::AID-IMMU787>3.0.CO;2-I. View

16.

Morita S, Kojima T, Kitamura T . Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000; 7(12):1063-6. DOI: 10.1038/sj.gt.3301206. View

17.

Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R . 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; 192(3):337-46. PMC: 2193227. DOI: 10.1084/jem.192.3.337. View

18.

Tangye S, Phillips J, Lanier L, Nichols K . Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J Immunol. 2000; 165(6):2932-6. DOI: 10.4049/jimmunol.165.6.2932. View

19.

Benoit L, Wang X, PABST H, Dutz J, Tan R . Defective NK cell activation in X-linked lymphoproliferative disease. J Immunol. 2000; 165(7):3549-53. DOI: 10.4049/jimmunol.165.7.3549. View

20.

Nakajima H, Cella M, Bouchon A, Grierson H, Lewis J, Duckett C . Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity. Eur J Immunol. 2000; 30(11):3309-18. DOI: 10.1002/1521-4141(200011)30:11<3309::AID-IMMU3309>3.0.CO;2-3. View