J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/06/2053/08 $2.00
Volume 185, Number 12, June 16, 1997 2053-2060

A New Mechanism of NK Cell Cytotoxicity Activation: The CD40-CD40 Ligand Interaction

By Ennio Carbone,^* Giuseppina Ruggiero,^* Giuseppe Terrazzano,^* Carmen Palomba,^* Ciro Manzo, Silvia Fontana,^§ Hergen Spits, Klas Kärre,^¶ and Serafino Zappacosta^*

From the ^* Cattedra di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy;  Oncologia Sperimentale C, Immunologia, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; ^§ Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy;  Division of Immunology, The Netherlands Cancer Institute, Amsterdam, Holland; and ^¶ Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2-activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2-activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.

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

This article has been cited by other articles:

• Gong, Y.-F., Xiang, L.-X., Shao, J.-Z. (2009). CD154-CD40 Interactions Are Essential for Thymus-Dependent Antibody Production in Zebrafish: Insights into the Origin of Costimulatory Pathway in Helper T Cell-Regulated Adaptive Immunity in Early Vertebrates. J. Immunol. 182: 7749-7762 [Abstract] [Full Text]  
• La Rocca, R., Fulciniti, M., Lakshmikanth, T., Mesuraca, M., Ali, T. H., Mazzei, V., Amodio, N., Catalano, L., Rotoli, B., Ouerfelli, O., Grieco, M., Gulletta, E., Bond, H. M., Morrone, G., Ferrone, S., Carbone, E. (2009). Early Hematopoietic Zinc Finger Protein Prevents Tumor Cell Recognition by Natural Killer Cells. J. Immunol. 182: 4529-4537 [Abstract] [Full Text]  
• Takahara, M., Miyai, M., Tomiyama, M., Mutou, M., Nicol, A. J., Nieda, M. (2008). Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via V{gamma}9{gamma}{delta} T cell activation. J. Leukoc. Biol. 83: 742-754 [Abstract] [Full Text]  
• Li, S., Yan, Y., Lin, Y., Bullens, D. M., Rutgeerts, O., Goebels, J., Segers, C., Boon, L., Kasran, A., De Vos, R., Dewolf-Peeters, C., Waer, M., Billiau, A. D. (2007). Rapidly induced, T-cell independent xenoantibody production is mediated by marginal zone B cells and requires help from NK cells. Blood 110: 3926-3935 [Abstract] [Full Text]  
• Baltz, K. M., Krusch, M., Bringmann, A., Brossart, P., Mayer, F., Kloss, M., Baessler, T., Kumbier, I., Peterfi, A., Kupka, S., Kroeber, S., Menzel, D., Radsak, M. P., Rammensee, H.-G., Salih, H. R. (2007). Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions. FASEB J. 21: 2442-2454 [Abstract] [Full Text]  
• Shen, L., Zhang, C., Wang, T., Brooks, S., Ford, R. J., Lin-Lee, Y. C., Kasianowicz, A., Kumar, V., Martin, L., Liang, P., Cowell, J., Ambrus, J. L. Jr (2006). Development of Autoimmunity in IL-14{alpha}-Transgenic Mice. J. Immunol. 177: 5676-5686 [Abstract] [Full Text]  
• Gao, N., Schwartzberg, P., Wilder, J. A., Blazar, B. R., Yuan, D. (2006). B Cell Induction of IL-13 Expression in NK Cells: Role of CD244 and SLAM-Associated Protein.. J. Immunol. 176: 2758-2764 [Abstract] [Full Text]  
• Rousseau, R. F., Biagi, E., Dutour, A., Yvon, E. S., Brown, M. P., Lin, T., Mei, Z., Grilley, B., Popek, E., Heslop, H. E., Gee, A. P., Krance, R. A., Popat, U., Carrum, G., Margolin, J. F., Brenner, M. K. (2006). Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood 107: 1332-1341 [Abstract] [Full Text]  
• Tai, Y.-T., Li, X.-F., Catley, L., Coffey, R., Breitkreutz, I., Bae, J., Song, W., Podar, K., Hideshima, T., Chauhan, D., Schlossman, R., Richardson, P., Treon, S. P., Grewal, I. S., Munshi, N. C., Anderson, K. C. (2005). Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments Anti-CD40 SGN-40-Induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications. Cancer Res. 65: 11712-11720 [Abstract] [Full Text]  
• Atochina, O., Harn, D. (2005). LNFPIII/LeX-Stimulated Macrophages Activate Natural Killer Cells via CD40-CD40L Interaction. CVI 12: 1041-1049 [Abstract] [Full Text]  
• Esplugues, E., Vega-Ramos, J., Cartoixa, D., Vazquez, B. N., Salaet, I., Engel, P., Lauzurica, P. (2005). Induction of tumor NK-cell immunity by anti-CD69 antibody therapy. Blood 105: 4399-4406 [Abstract] [Full Text]  
• Nowbakht, P., Ionescu, M.-C. S., Rohner, A., Kalberer, C. P., Rossy, E., Mori, L., Cosman, D., De Libero, G., Wodnar-Filipowicz, A. (2005). Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 105: 3615-3622 [Abstract] [Full Text]  
• Gao, N., Dang, T., Dunnick, W. A., Collins, J. T., Blazar, B. R., Yuan, D. (2005). Receptors and Counterreceptors Involved in NK-B Cell Interactions. J. Immunol. 174: 4113-4119 [Abstract] [Full Text]  
• Carbone, E., Neri, P., Mesuraca, M., Fulciniti, M. T., Otsuki, T., Pende, D., Groh, V., Spies, T., Pollio, G., Cosman, D., Catalano, L., Tassone, P., Rotoli, B., Venuta, S. (2005). HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 105: 251-258 [Abstract] [Full Text]  
• Garcia, P., de Heredia, A. B., Bellon, T., Carpio, E., Llano, M., Caparros, E., Aparicio, P., Lopez-Botet, M. (2004). Signalling via CD70, a member of the TNF family, regulates T cell functions. J. Leukoc. Biol. 76: 263-270 [Abstract] [Full Text]  
• Brady, J., Hayakawa, Y., Smyth, M. J., Nutt, S. L. (2004). IL-21 Induces the Functional Maturation of Murine NK Cells. J. Immunol. 172: 2048-2058 [Abstract] [Full Text]  
• Lee, B. O., Moyron-Quiroz, J., Rangel-Moreno, J., Kusser, K. L., Hartson, L., Sprague, F., Lund, F. E., Randall, T. D. (2003). CD40, but Not CD154, Expression on B Cells Is Necessary for Optimal Primary B Cell Responses. J. Immunol. 171: 5707-5717 [Abstract] [Full Text]  
• Contin, C., Pitard, V., Itai, T., Nagata, S., Moreau, J.-F., Dechanet-Merville, J. (2003). Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-{alpha}-converting Enzyme: IMPLICATIONS FOR CD40 SIGNALING. J. Biol. Chem. 278: 32801-32809 [Abstract] [Full Text]  
• Brice, G. T., Graber, N. L., Carucci, D. J., Doolan, D. L. (2002). Optimal induction of antigen-specific CD8+ T cell responses requires bystander cell participation. J. Leukoc. Biol. 72: 1164-1171 [Abstract] [Full Text]  
• Shirasugi, N., Adams, A. B., Durham, M. M., Lukacher, A. E., Xu, H., Rees, P., Cowan, S. R., Williams, M. A., Pearson, T. C., Larsen, C. P. (2002). Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens. J. Immunol. 169: 2677-2684 [Abstract] [Full Text]  
• Farag, S. S., Fehniger, T. A., Ruggeri, L., Velardi, A., Caligiuri, M. A. (2002). Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 100: 1935-1947 [Abstract] [Full Text]  
• Terrazzano, G., Zanzi, D., Palomba, C., Carbone, E., Grimaldi, S., Pisanti, S., Fontana, S., Zappacosta, S., Ruggiero, G. (2002). Differential involvement of CD40, CD80, and major histocompatibility complex class I molecules in cytotoxicity induction and interferon-{gamma} production by human natural killer effectors. J. Leukoc. Biol. 72: 305-311 [Abstract] [Full Text]  
• Pisegna, S., Zingoni, A., Pirozzi, G., Cinque, B., Cifone, M. G., Morrone, S., Piccoli, M., Frati, L., Palmieri, G., Santoni, A. (2002). Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells. J. Immunol. 169: 68-74 [Abstract] [Full Text]  
• Costa, C., Barber, D. F., Fodor, W. L. (2002). Human NK Cell-Mediated Cytotoxicity Triggered by CD86 and Gal{alpha}1,3-Gal Is Inhibited in Genetically Modified Porcine Cells. J. Immunol. 168: 3808-3816 [Abstract] [Full Text]  
• Gerosa, F., Baldani-Guerra, B., Nisii, C., Marchesini, V., Carra, G., Trinchieri, G. (2002). Reciprocal Activating Interaction between Natural Killer Cells and Dendritic Cells. JEM 195: 327-333 [Abstract] [Full Text]  
• Blanca, I. R., Bere, E. W., Young, H. A., Ortaldo, J. R. (2001). Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5+ B Cells. J. Immunol. 167: 6132-6139 [Abstract] [Full Text]  
• O'Gorman, M. R. G., DuChateau, B., Paniagua, M., Hunt, J., Bensen, N., Yogev, R. (2001). Abnormal CD40 Ligand (CD154) Expression in Human Immunodeficiency Virus-Infected Children. CVI 8: 1104-1109 [Abstract] [Full Text]  
• Koumas, L., King, A. E., Critchley, H. O. D., Kelly, R. W., Phipps, R. P. (2001). Fibroblast Heterogeneity : Existence of Functionally Distinct Thy 1+ and Thy 1- Human Female Reproductive Tract Fibroblasts. Am. J. Pathol. 159: 925-935 [Abstract] [Full Text]  
• Ntrivalas, E.I., Kwak-Kim, J.Y.H., Gilman-Sachs, A., Chung-Bang, H., Ng, S.C., Beaman, K.D., Mantouvalos, H.P., Beer, A.E. (2001). Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 16: 855-861 [Abstract] [Full Text]  
• Brill, K. J., Li, Q., Larkin, R., Canaday, D. H., Kaplan, D. R., Boom, W. H., Silver, R. F. (2001). Human Natural Killer Cells Mediate Killing of Intracellular Mycobacterium tuberculosis H37Rv via Granule-Independent Mechanisms. Infect. Immun. 69: 1755-1765 [Abstract] [Full Text]  
• Yu, Y., Hagihara, M., Ando, K., Gansuvd, B., Matsuzawa, H., Tsuchiya, T., Ueda, Y., Inoue, H., Hotta, T., Kato, S. (2001). Enhancement of Human Cord Blood CD34+ Cell-Derived NK Cell Cytotoxicity by Dendritic Cells. J. Immunol. 166: 1590-1600 [Abstract] [Full Text]  
• Turner, J. G., Rakhmilevich, A. L., Burdelya, L., Neal, Z., Imboden, M., Sondel, P. M., Yu, H. (2001). Anti-CD40 Antibody Induces Antitumor and Antimetastatic Effects: The Role of NK Cells. J. Immunol. 166: 89-94 [Abstract] [Full Text]  
• Zambello, R., Trentin, L., Facco, M., Siviero, M., Galvan, S., Piazza, F., Perin, A., Agostini, C., Semenzato, G. (2000). Analysis of TNF-receptor and ligand superfamily molecules in patients with lymphoproliferative disease of granular lymphocytes. Blood 96: 647-654 [Abstract] [Full Text]  
• Carbone, E., Terrazzano, G., Melian, A., Zanzi, D., Moretta, L., Porcelli, S., Karre, K., Zappacosta, S. (2000). Inhibition of Human NK Cell-Mediated Killing by CD1 Molecules. J. Immunol. 164: 6130-6137 [Abstract] [Full Text]  
• Yu, T.-K., Caudell, E. G., Smid, C., Grimm, E. A. (2000). IL-2 Activation of NK Cells: Involvement of MKK1/2/ERK But Not p38 Kinase Pathway. J. Immunol. 164: 6244-6251 [Abstract] [Full Text]  
• Pirozzi, G., Lombari, V., Zanzi, D., Ionna, F., Lombardi, M. L., Errico, S., Ruggiero, G., Manzo, C. (2000). CD40 expressed on human melanoma cells mediates T cell co-stimulation and tumor cell growth. Int Immunol 12: 787-795 [Abstract] [Full Text]  
• Szomolanyi-Tsuda, E., Brien, J. D., Dorgan, J. E., Welsh, R. M., Garcea, R. L. (2000). The Role of CD40-CD154 Interaction in Antiviral T Cell-Independent IgG Responses. J. Immunol. 164: 5877-5882 [Abstract] [Full Text]  
• Gays, F., Unnikrishnan, M., Shrestha, S., Fraser, K. P., Brown, A. R., Tristram, C. M. G., Chrzanowska-Lightowlers, Z. M. A., Brooks, C. G. (2000). The Mouse Tumor Cell Lines EL4 and RMA Display Mosaic Expression of NK-Related and Certain Other Surface Molecules and Appear to Have a Common Origin. J. Immunol. 164: 5094-5102 [Abstract] [Full Text]  
• Urashima, M., Suzuki, H., Yuza, Y., Akiyama, M., Ohno, N., Eto, Y. (2000). An oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium. Blood 95: 1258-1263 [Abstract] [Full Text]  
• Wilson, J. L., Heffler, L. C., Charo, J., Scheynius, A., Bejarano, M.-T., Ljunggren, H.-G. (1999). Targeting of Human Dendritic Cells by Autologous NK Cells. J. Immunol. 163: 6365-6370 [Abstract] [Full Text]  
• Wilson, J. L., Charo, J., Martin-Fontecha, A., Dellabona, P., Casorati, G., Chambers, B. J., Kiessling, R., Bejarano, M.-T., Ljunggren, H.-G. (1999). NK Cell Triggering by the Human Costimulatory Molecules CD80 and CD86. J. Immunol. 163: 4207-4212 [Abstract] [Full Text]  
• Nieto, M., Rodriguez-Fernandez, J. L., Navarro, F., Sancho, D., Frade, J. M.R., Mellado, M., Martinez-A, C., Cabanas, C., Sanchez-Madrid, F. (1999). Signaling Through CD43 Induces Natural Killer Cell Activation, Chemokine Release, and PYK-2 Activation. Blood 94: 2767-2777 [Abstract] [Full Text]  
• Martin-Fontecha, A., Assarsson, E., Carbone, E., Karre, K., Ljunggren, H.-G. (1999). Triggering of Murine NK Cells by CD40 and CD86 (B7-2). J. Immunol. 162: 5910-5916 [Abstract] [Full Text]  
• Mandelboim, O., Malik, P., Davis, D. M., Jo, C. H., Boyson, J. E., Strominger, J. L. (1999). Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc. Natl. Acad. Sci. USA 96: 5640-5644 [Abstract] [Full Text]  
• Maxwell, J. R., Campbell, J. D., Kim, C. H., Vella, A. T. (1999). CD40 Activation Boosts T Cell Immunity In Vivo by Enhancing T Cell Clonal Expansion and Delaying Peripheral T Cell Deletion. J. Immunol. 162: 2024-2034 [Abstract] [Full Text]  
• ROSSINI, A. A., GREINER, D. L., MORDES, J. P. (1999). Induction of Immunologic Tolerance for Transplantation. Physiol. Rev. 79: 99-141 [Abstract] [Full Text]  
• Hoshino, T., Winkler-Pickett, R. T., Mason, A. T., Ortaldo, J. R., Young, H. A. (1999). IL-13 Production by NK Cells: IL-13-Producing NK and T Cells Are Present In Vivo in the Absence of IFN-{gamma}. J. Immunol. 162: 51-59 [Abstract] [Full Text]  
• Vitale, M., Bottino, C., Sivori, S., Sanseverino, L., Castriconi, R., Marcenaro, E., Augugliaro, R., Moretta, L., Moretta, A. (1998). NKp44, a Novel Triggering Surface Molecule Specifically Expressed by Activated Natural Killer Cells, Is Involved in Non-Major Histocompatibility Complex-restricted Tumor Cell Lysis. JEM 187: 2065-2072 [Abstract] [Full Text]  
• Kalled, S. L., Cutler, A. H., Datta, S. K., Thomas, D. W. (1998). Anti-CD40 Ligand Antibody Treatment of SNF1 Mice with Established Nephritis: Preservation of Kidney Function. J. Immunol. 160: 2158-2165 [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]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS