Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion.
Journal: 2006/January - Blood
ISSN: 0006-4971
Abstract:
Freshly isolated, resting natural killer (NK) cells are generally less lytic against target cells than in vitro interleukin 2 (IL-2)-activated NK cells. To investigate the basis for this difference, the contribution of several receptors to activation of human NK cells was examined. Target-cell lysis by IL-2-activated NK cells in a redirected, antibody-dependent cytotoxicity assay was triggered by a number of receptors. In contrast, cytotoxicity by resting NK cells was induced only by CD16, and not by NKp46, NKG2D, 2B4 (CD244), DNAM-1 (CD226), or CD2. Calcium flux in resting NK cells was induced with antibodies to CD16 and, to a weaker extent, antibodies to NKp46 and 2B4. Although NKp46 did not enhance CD16-mediated calcium flux, it synergized with all other receptors. 2B4 synergized with 3 other receptors, NKG2D and DNAM-1 each synergized with 2 other receptors, and CD2 synergized with NKp46 only. Resting NK cells were induced to secrete tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), and to kill target cells by engagement of specific, pair-wise combinations of receptors. Therefore, natural cytotoxicity by resting NK cells is induced only by mutual costimulation of nonactivating receptors. These results reveal distinct and specific patterns of synergy among receptors on resting NK cells.
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Blood 107(1): 159-166

Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion

From the Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and the Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Reprints: Eric O. Long, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, 12441 Parklawn Dr, Rockville, MD 20852; e-mail: vog.hin@gnole.
Reprints: Eric O. Long, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, 12441 Parklawn Dr, Rockville, MD 20852; e-mail: vog.hin@gnole.
Received 2005 Apr 1; Accepted 2005 Aug 28.

Abstract

Freshly isolated, resting natural killer (NK) cells are generally less lytic against target cells than in vitro interleukin 2 (IL-2)-activated NK cells. To investigate the basis for this difference, the contribution of several receptors to activation of human NK cells was examined. Target-cell lysis by IL-2-activated NK cells in a redirected, antibody-dependent cytotoxicity assay was triggered by a number of receptors. In contrast, cytotoxicity by resting NK cells was induced only by CD16, and not by NKp46, NKG2D, 2B4 (CD244), DNAM-1 (CD226), or CD2. Calcium flux in resting NK cells was induced with antibodies to CD16 and, to a weaker extent, antibodies to NKp46 and 2B4. Although NKp46 did not enhance CD16-mediated calcium flux, it synergized with all other receptors. 2B4 synergized with 3 other receptors, NKG2D and DNAM-1 each synergized with 2 other receptors, and CD2 synergized with NKp46 only. Resting NK cells were induced to secrete tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), and to kill target cells by engagement of specific, pair-wise combinations of receptors. Therefore, natural cytotoxicity by resting NK cells is induced only by mutual costimulation of nonactivating receptors. These results reveal distinct and specific patterns of synergy among receptors on resting NK cells.

Abstract

Acknowledgments

We thank A. Das, S. Rajagopalan, P. Srinivasan, and S. Vielkind for help in NK-cell isolation.

Acknowledgments

Notes

Prepublished online as Blood First Edition Paper, September 8, 2005; DOI 10.1182/blood-2005-04-1351.

Supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), NIH-Karolinska Institutet Graduate Partnership Program (Y.T.B.), and Swedish Foundation for Strategic Research, Research Council, and Cancer Society (H.G.L.).

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

Notes
Prepublished online as Blood First Edition Paper, September 8, 2005; DOI 10.1182/blood-2005-04-1351.
Supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), NIH-Karolinska Institutet Graduate Partnership Program (Y.T.B.), and Swedish Foundation for Strategic Research, Research Council, and Cancer Society (H.G.L.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

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