J. Exp. Med.
Volume 184 December 1996 2119-2128

The Ly-49D Receptor Activates Murine Natural Killer Cells

By L.H. Mason,^* S.K. Anderson,^§ W.M. Yokoyama, H.R.C. Smith, R. Winkler-Pickett,^* and J.R. Ortaldo^*

From the ^* Laboratory of Experimental Immunology, Division of Basic Sciences, and  Intramural Research Support Program, SAIC Frederick, National Cancer Institute-FCRDC, Frederick, Maryland 21702-1201; ^§ Division of Rheumatology, Washington University, St. Louis, Missouri 63110

Proteins encoded by members of the Ly-49 gene family are predominantly expressed on murine natural killer (NK) cells. Several members of this gene family have been demonstrated to inhibit NK cell lysis upon recognizing their class I ligands on target cells. In this report, we present data supporting that not all Ly-49 proteins inhibit NK cell function. Our laboratory has generated and characterized a monoclonal antibody (mAb) (12A8) that can be used to recognize the Ly-49D subset of murine NK cells. Transfection of Cos-7 cells with known members of the Ly-49 gene family revealed that 12A8 recognizes Ly-49D, but also cross-reacts with the Ly-49A protein on B6 NK cells. In addition, 12A8 demonstrates reactivity by both immunoprecipitation and two-color flow cytometry analysis with an NK cell subset that is distinct from those expressing Ly-49A, C, or G2. An Ly-49D⁺ subset of NK cells that did not express Ly49A, C, and G2 was isolated and examined for their functional capabilities. Tumor targets and concanovalin A (ConA) lymphoblasts from a variety of H2 haplotypes were examined for their susceptibility to lysis by Ly-49D⁺ NK cells. None of the major histocompatibility complex class I-bearing targets inhibited lysis of Ly-49D⁺ NK cells. More importantly, we demonstrate that the addition of mAb 12A8 to Ly-49D⁺ NK cells can augment lysis of FcR⁺ target cells in a reverse antibody-dependent cellular cytotoxicity-type assay and induces apoptosis in Ly49D⁺ NK cells. Furthermore, the cytoplasmic domain of Ly-49D does not contain the V/IxYxxL immunoreceptor tyrosine-based inhibitory motif found in Ly-49A, C, or G2 that has been characterized in the human p58 killer inhibitory receptors. Therefore, Ly-49D is the first member of the Ly-49 family characterized as transmitting positive signals to NK cells, rather than inhibiting NK cell function.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Merck, E., Voyle, R. B., MacDonald, H. R. (2009). Ly49D Engagement on T Lymphocytes Induces TCR-Independent Activation and CD8 Effector Functions That Control Tumor Growth. J. Immunol. 182: 183-192 [Abstract] [Full Text]  
• Guo, H., Samarakoon, A., Vanhaesebroeck, B., Malarkannan, S. (2008). The p110{delta} of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. JEM 205: 2419-2435 [Abstract] [Full Text]  
• Malarkannan, S., Regunathan, J., Chu, H., Kutlesa, S., Chen, Y., Zeng, H., Wen, R., Wang, D. (2007). Bcl10 Plays a Divergent Role in NK Cell-Mediated Cytotoxicity and Cytokine Generation. J. Immunol. 179: 3752-3762 [Abstract] [Full Text]  
• Chewning, J. H., Gudme, C. N., Hsu, K. C., Selvakumar, A., Dupont, B. (2007). KIR2DS1-Positive NK Cells Mediate Alloresponse against the C2 HLA-KIR Ligand Group In Vitro. J. Immunol. 179: 854-868 [Abstract] [Full Text]  
• Regunathan, J., Chen, Y., Kutlesa, S., Dai, X., Bai, L., Wen, R., Wang, D., Malarkannan, S. (2006). Differential and Nonredundant Roles of Phospholipase C{gamma}2 and Phospholipase C{gamma}1 in the Terminal Maturation of NK Cells. J. Immunol. 177: 5365-5376 [Abstract] [Full Text]  
• Lokshin, A., Raskovalova, T., Huang, X., Zacharia, L. C., Jackson, E. K., Gorelik, E. (2006). Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells.. Cancer Res. 66: 7758-7765 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Taylor, L. S., McVicar, D. W. (2006). Regulation of Ly49D/DAP12 Signal Transduction by Src-Family Kinases and CD45.. J. Immunol. 176: 6615-6623 [Abstract] [Full Text]  
• Fan, Z., Yu, P., Wang, Y., Wang, Y., Fu, M. L., Liu, W., Sun, Y., Fu, Y.-X. (2006). NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood 107: 1342-1351 [Abstract] [Full Text]  
• Ortaldo, J. R., Winkler-Pickett, R., Wigginton, J., Horner, M., Bere, E. W., Mason, A. T., Bhat, N., Cherry, J., Sanford, M., Hodge, D. L., Young, H. A. (2006). Regulation of ITAM-positive receptors: role of IL-12 and IL-18. Blood 107: 1468-1475 [Abstract] [Full Text]  
• Hart, G., Flaishon, L., Becker-Herman, S., Shachar, I. (2005). Tight Regulation of IFN-{gamma} Transcription and Secretion in Immature and Mature B cells by the Inhibitory MHC Class I Receptor, Ly49G2. J. Immunol. 175: 5034-5042 [Abstract] [Full Text]  
• Huang, Y., Rezzoug, F., Xu, H., Chilton, P. M., Schanie, C. L., Fugier-Vivier, I., Ildstad, S. T. (2005). NK Cells Play a Critical Role in the Regulation of Class I-Deficient Hemopoietic Stem Cell Engraftment: Evidence for NK Tolerance Correlates with Receptor Editing. J. Immunol. 175: 3753-3761 [Abstract] [Full Text]  
• Xie, X., He, H., Colonna, M., Seya, T., Takai, T., Croy, B. A. (2005). Pathways Participating in Activation of Mouse Uterine Natural Killer Cells During Pregnancy. Biol. Reprod. 73: 510-518 [Abstract] [Full Text]  
• Brehm, M. A., Daniels, K. A., Ortaldo, J. R., Welsh, R. M. (2005). Rapid Conversion of Effector Mechanisms from NK to T Cells during Virus-Induced Lysis of Allogeneic Implants In Vivo. J. Immunol. 174: 6663-6671 [Abstract] [Full Text]  
• Regunathan, J., Chen, Y., Wang, D., Malarkannan, S. (2005). NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Blood 105: 233-240 [Abstract] [Full Text]  
• Han, Y., Zhang, M., Li, N., Chen, T., Zhang, Y., Wan, T., Cao, X. (2004). KLRL1, a novel killer cell lectinlike receptor, inhibits natural killer cell cytotoxicity. Blood 104: 2858-2866 [Abstract] [Full Text]  
• Johansson, S. E., Hall, H., Bjorklund, J., Hoglund, P. (2004). Broadly impaired NK cell function in non-obese diabetic mice is partially restored by NK cell activation in vivo and by IL-12/IL-18 in vitro. Int Immunol 16: 1-11 [Abstract] [Full Text]  
• Gao, J.-X., Liu, X., Wen, J., Caligiuri, M. A., Stroynowski, I., Zheng, P., Liu, Y. (2003). Two-signal requirement for activation and effector function of natural killer cell response to allogeneic tumor cells. Blood 102: 4456-4463 [Abstract] [Full Text]  
• Hart, G., Flaishon, L., Becker-Herman, S., Shachar, I. (2003). Ly49D Receptor Expressed on Immature B Cells Regulates Their IFN-{gamma} Secretion, Actin Polymerization, and Homing. J. Immunol. 171: 4630-4638 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Anderson, S. K., Alvord, W. G., Klabansky, R. L., Young, H. A., Ortaldo, J. R. (2003). Receptor Glycosylation Regulates Ly-49 Binding to MHC Class I. J. Immunol. 171: 4235-4242 [Abstract] [Full Text]  
• Inngjerdingen, M., Rolstad, B., Ryan, J. C. (2003). Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12. J. Immunol. 171: 2889-2895 [Abstract] [Full Text]  
• Westgaard, I. H., Dissen, E., Torgersen, K. M., Lazetic, S., Lanier, L. L., Phillips, J. H., Fossum, S. (2003). The Lectin-like Receptor KLRE1 Inhibits Natural Killer Cell Cytotoxicity. JEM 197: 1551-1561 [Abstract] [Full Text]  
• Zhao, Y., Ohdan, H., Manilay, J. O., Sykes, M. (2003). NK Cell Tolerance in Mixed Allogeneic Chimeras. J. Immunol. 170: 5398-5405 [Abstract] [Full Text]  
• Ortaldo, J. R., Young, H. A. (2003). Expression of IFN-{gamma} Upon Triggering of Activating Ly49D NK Receptors In Vitro and In Vivo: Costimulation with IL-12 or IL-18 Overrides Inhibitory Receptors. J. Immunol. 170: 1763-1769 [Abstract] [Full Text]  
• McVicar, D. W., Winkler-Pickett, R., Taylor, L. S., Makrigiannis, A., Bennett, M., Anderson, S. K., Ortaldo, J. R. (2002). Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice. J. Immunol. 169: 1721-1728 [Abstract] [Full Text]  
• Fahlen, L., Lendahl, U., Sentman, C. L. (2001). MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells. J. Immunol. 166: 6585-6592 [Abstract] [Full Text]  
• Ortaldo, J. R., Bere, E. W., Hodge, D., Young, H. A. (2001). Activating Ly-49 NK Receptors: Central Role in Cytokine and Chemokine Production. J. Immunol. 166: 4994-4999 [Abstract] [Full Text]  
• Makrigiannis, A. P., Pau, A. T., Saleh, A., Winkler-Pickett, R., Ortaldo, J. R., Anderson, S. K. (2001). Class I MHC-Binding Characteristics of the 129/J Ly49 Repertoire. J. Immunol. 166: 5034-5043 [Abstract] [Full Text]  
• Silver, E. T., Gong, D.-E., Hazes, B., Kane, K. P. (2001). Ly-49W, an Activating Receptor of Nonobese Diabetic Mice With Close Homology to the Inhibitory Receptor Ly-49G, Recognizes H-2Dk and H-2Dd. J. Immunol. 166: 2333-2341 [Abstract] [Full Text]  
• Ortaldo, J. R., Winkler-Pickett, R., Wiegand, G. (2000). Activating Ly-49D NK receptors: expression and function in relation to ontogeny and Ly-49 inhibitor receptors. J. Leukoc. Biol. 68: 748-756 [Abstract] [Full Text]  
• Makrigiannis, A. P., Etzler, J., Winkler-Pickett, R., Mason, A., Ortaldo, J. R., Anderson, S. K. (2000). Identification of the Ly49L protein: evidence for activating counterparts to inhibitory Ly49 proteins. J. Leukoc. Biol. 68: 765-771 [Abstract] [Full Text]  
• Mason, L. H. (2000). Recognition of CHO cells by inhibitory and activating Ly-49 receptors. J. Leukoc. Biol. 68: 583-586 [Abstract] [Full Text]  
• Silver, E. T., Gong, D.-E., Chang, C. S., Amrani, A., Santamaria, P., Kane, K. P. (2000). Ly-49P Activates NK-Mediated Lysis by Recognizing H-2Dd 1. J. Immunol. 165: 1771-1781 [Abstract] [Full Text]  
• Backman-Petersson, E., Butcher, G. W., Hedlund, G. (2000). Self-MHC class Ia (RT1-An) protects cells co-expressing the activatory allogeneic MHC class Ib molecule (RT1-Eu) from NK lysis. Int Immunol 12: 843-850 [Abstract] [Full Text]  
• Smith, H. R.C., Chuang, H. H., Wang, L. L., Salcedo, M., Heusel, J. W., Yokoyama, W. M. (2000). Nonstochastic Coexpression of Activation Receptors on Murine Natural Killer Cells. JEM 191: 1341-1354 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Mason, A. T., McVicar, D., Ortaldo, J. R. (2000). Interaction of Ly-49D+ NK Cells with H-2Dd Target Cells Leads to Dap-12 Phosphorylation and IFN-{gamma} Secretion. J. Immunol. 164: 603-611 [Abstract] [Full Text]  
• Korten, S., Wilk, E., Gessner, J. E., Meyer, D., Schmidt, R. E. (1999). Altered Donor and Recipient Ly49+ NK Cell Subsets in Allogeneic H-2d -> H-2b and H-2b -> H-2d Bone Marrow Chimeras. J. Immunol. 163: 5896-5905 [Abstract] [Full Text]  
• Ortaldo, J. R., Winkler-Pickett, R., Willette-Brown, J., Wange, R. L., Anderson, S. K., Palumbo, G. J., Mason, L. H., McVicar, D. W. (1999). Structure/Function Relationship of Activating Ly-49D and Inhibitory Ly-49G2 NK Receptors ,2. J. Immunol. 163: 5269-5277 [Abstract] [Full Text]  
• Nakamura, M. C., Naper, C., Niemi, E. C., Spusta, S. C., Rolstad, B., Butcher, G. W., Seaman, W. E., Ryan, J. C. (1999). Natural Killing of Xenogeneic Cells Mediated by the Mouse Ly-49D Receptor. J. Immunol. 163: 4694-4700 [Abstract] [Full Text]  
• Makrigiannis, A. P., Gosselin, P., Mason, L. H., Taylor, L. S., McVicar, D. W., Ortaldo, J. R., Anderson, S. K. (1999). Cloning and Characterization of a Novel Activating Ly49 Closely Related to Ly49A ,2 ,3. J. Immunol. 163: 4931-4938 [Abstract] [Full Text]  
• Depatie, C., Chalifour, A., Pare, C., Lee, S.-H., Vidal, S. M., Lemieux3, S. (1999). Assessment of Cmv1 candidates by genetic mapping and in vivo antibody depletion of NK cell subsets. Int Immunol 11: 1541-1551 [Abstract] [Full Text]  
• Manilay, J. O., Waneck, G. L., Sykes, M. (1999). Levels of Ly-49 Receptor Expression Are Determined by the Frequency of Interactions with MHC Ligands: Evidence Against Receptor Calibration to a ""Useful"" Level. J. Immunol. 163: 2628-2633 [Abstract] [Full Text]  
• Williams, N. S., Klem, J., Puzanov, I. J., Sivakumar, P. V., Bennett, M., Kumar, V. (1999). Differentiation of NK1.1+, Ly49+ NK Cells from flt3+ Multipotent Marrow Progenitor Cells. J. Immunol. 163: 2648-2656 [Abstract] [Full Text]  
• Taylor, L. S., McVicar, D. W. (1999). Functional Association of Fcvarepsilon RIgamma With Arginine632 of Paired Immunoglobulin-Like Receptor (PIR)-A3 in Murine Macrophages. Blood 94: 1790-1796 [Abstract] [Full Text]  
• Bakker, A. B. H., Baker, E., Sutherland, G. R., Phillips, J. H., Lanier, L. L. (1999). Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc. Natl. Acad. Sci. USA 96: 9792-9796 [Abstract] [Full Text]  
• George, T. C., Ortaldo, J. R., Lemieux, S., Kumar, V., Bennett, M. (1999). Tolerance and Alloreactivity of the Ly49D Subset of Murine NK Cells. J. Immunol. 163: 1859-1867 [Abstract] [Full Text]  
• Kubota, A., Kubota, S., Lohwasser, S., Mager, D. L., Takei, F. (1999). Diversity of NK Cell Receptor Repertoire in Adult and Neonatal Mice. J. Immunol. 163: 212-216 [Abstract] [Full Text]  
• Olsson-Alheim, M. Y., Sundback, J., Karre, K., Sentman, C. L. (1999). The MHC Class I Molecule H-2Dp Inhibits Murine NK Cells via the Inhibitory Receptor Ly49A. J. Immunol. 162: 7010-7014 [Abstract] [Full Text]  
• Lian, R. H., Li, Y., Kubota, S., Mager, D. L., Takei, F. (1999). Recognition of Class I MHC by NK Receptor Ly-49C: Identification of Critical Residues. J. Immunol. 162: 7271-7276 [Abstract] [Full Text]  
• Idris, A. H., Smith, H. R. C., Mason, L. H., Ortaldo, J. R., Scalzo, A. A., Yokoyama, W. M. (1999). The natural killer gene complex genetic locus Chok encodes Ly-49D, a target recognition receptor that activates natural killing. Proc. Natl. Acad. Sci. USA 96: 6330-6335 [Abstract] [Full Text]  
• Kung, S. K. P., Su, R.-C., Shannon, J., Miller, R. G. (1999). The NKR-P1B Gene Product Is an Inhibitory Receptor on SJL/J NK Cells. J. Immunol. 162: 5876-5887 [Abstract] [Full Text]  
• Carlyle, J. R., Martin, A., Mehra, A., Attisano, L., Tsui, F. W., Zuniga-Pflucker, J. C. (1999). Mouse NKR-P1B, a Novel NK1.1 Antigen with Inhibitory Function. J. Immunol. 162: 5917-5923 [Abstract] [Full Text]  
• Lo, W.-F., Ong, H., Metcalf, E. S., Soloski, M. J. (1999). T Cell Responses to Gram-Negative Intracellular Bacterial Pathogens: A Role for CD8+ T Cells in Immunity to Salmonella Infection and the Involvement of MHC Class Ib Molecules. J. Immunol. 162: 5398-5406 [Abstract] [Full Text]  
• Schatzle, J. D., Sheu, S., Stepp, S. E., Mathew, P. A., Bennett, M., Kumar, V. (1999). Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4. Proc. Natl. Acad. Sci. USA 96: 3870-3875 [Abstract] [Full Text]  
• George, T. C., Mason, L. H., Ortaldo, J. R., Kumar, V., Bennett, M. (1999). Positive Recognition of MHC Class I Molecules by the Ly49D Receptor of Murine NK Cells. J. Immunol. 162: 2035-2043 [Abstract] [Full Text]  
• Nakamura, M. C., Linnemeyer, P. A., Niemi, E. C., Mason, L. H., Ortaldo, J. R., Ryan, J. C., Seaman, W. E. (1999). Mouse Ly-49D Recognizes H-2Dd and Activates Natural Killer Cell Cytotoxicity. JEM 189: 493-500 [Abstract] [Full Text]  
• Tay, C. H., Yu, L. Y. Y., Kumar, V., Mason, L., Ortaldo, J. R., Welsh, R. M. (1999). The Role of LY49 NK Cell Subsets in the Regulation of Murine Cytomegalovirus Infections. J. Immunol. 162: 718-726 [Abstract] [Full Text]  
• Idris, A. H., Iizuka, K., Smith, H. R.C., Scalzo, A. A., Yokoyama, W. M. (1998). Genetic Control Of Natural Killing and In Vivo Tumor Elimination by the Chok Locus. JEM 188: 2243-2256 [Abstract] [Full Text]  
• McVicar, D. W., Taylor, L. S., Gosselin, P., Willette-Brown, J., Mikhael, A. I., Geahlen, R. L., Nakamura, M. C., Linnemeyer, P., Seaman, W. E., Anderson, S. K., Ortaldo, J. R., Mason, L. H. (1998). DAP12-mediated Signal Transduction in Natural Killer Cells. A DOMINANT ROLE FOR THE Syk PROTEIN-TYROSINE KINASE. J. Biol. Chem. 273: 32934-32942 [Abstract] [Full Text]  
• Mainiero, F., Gismondi, A., Soriani, A., Cippitelli, M., Palmieri, G., Jacobelli, J., Piccoli, M., Frati, L., Santoni, A. (1998). Integrin-mediated Ras-Extracellular Regulated Kinase (ERK) Signaling Regulates Interferon gamma  Production in Human Natural Killer Cells. JEM 188: 1267-1275 [Abstract] [Full Text]  
• Smith, K. M., Wu, J., Bakker, A. B. H., Phillips, J. H., Lanier, L. L. (1998). Cutting Edge: Ly-49D and Ly-49H Associate with Mouse DAP12 and Form Activating Receptors. J. Immunol. 161: 7-10 [Abstract] [Full Text]  
• Yu, C.-R., Kirken, R. A., Malabarba, M. G., Young, H. A., Ortaldo, J. R. (1998). Differential Regulation of the Janus Kinase-STAT Pathway and Biologic Function of IL-13 in Primary Human NK and T Cells: A Comparative Study with IL-4. J. Immunol. 161: 218-227 [Abstract] [Full Text]  
• Robson MacDonald, H., Lees, R. K., Held, W. (1998). Developmentally Regulated Extinction of Ly-49 Receptor Expression Permits Maturation and Selection of NK1.1+ T Cells. JEM 187: 2109-2114 [Abstract] [Full Text]  
• Ho, E. L., Heusel, J. W., Brown, M. G., Matsumoto, K., Scalzo, A. A., Yokoyama, W. M. (1998). Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Proc. Natl. Acad. Sci. USA 95: 6320-6325 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Anderson, S. K., Gosselin, P., Shores, E. W., Love, P. E., Ortaldo, J. R., McVicar, D. W. (1998). Cutting Edge: Characterization of an Associated 16-kDa Tyrosine Phosphoprotein Required for Ly-49D Signal Transduction. J. Immunol. 160: 4148-4152 [Abstract] [Full Text]  
• Manoussaka, M. S., Smith, R. J., Conlin, V., Toomey, J. A., Brooks, C. G. (1998). Fetal Mouse NK Cell Clones Are Deficient in Ly49 Expression, Share a Common Broad Lytic Specificity, and Undergo Continuous and Extensive Diversification In Vitro. J. Immunol. 160: 2197-2206 [Abstract] [Full Text]  
• Naper, C., Ryan, J. C., Nakamura, M. C., Lambracht, D., Rolstad, B., Vaage, J. T. (1998). Identification of an Inhibitory MHC Receptor on Alloreactive Rat Natural Killer Cells. J. Immunol. 160: 219-224 [Abstract] [Full Text]  
• Arase, N., Arase, H., Park, S. Y., Ohno, H., Ra, C., Saito, T. (1997). Association with FcRgamma Is Essential for Activation Signal through NKR-P1 (CD161) in Natural Killer (NK) Cells and NK1.1+ T Cells. JEM 186: 1957-1963 [Abstract] [Full Text]  
• Brumbaugh, K. M., Binstadt, B. A., Billadeau, D. D., Schoon, R. A., Dick, C. J., Ten, R. M., Leibson, P. J. (1997). Functional Role for Syk Tyrosine Kinase in Natural Killer Cell-mediated Natural Cytotoxicity. JEM 186: 1965-1974 [Abstract] [Full Text]  
• Yokoyama, W. M. (1997). What Goes Up Must Come Down: The Emerging Spectrum of Inhibitory Receptors. JEM 186: 1803-1808 [Full Text]  
• Sivori, S., Vitale, M., Morelli, L., Sanseverino, L., Augugliaro, R., Bottino, C., Moretta, L., Moretta, A. (1997). p46, a Novel Natural Killer Cell-specific Surface Molecule That Mediates Cell Activation. JEM 186: 1129-1136 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS