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Original Article

IRIS, Department of Immunology, Chiron S.p.A., 53100 Siena, Italy

Address correspondence to N.M. Valiante, Immunology and Infectious Disease Research, Mail Stop 4.3, Chiron Corp., 4560 Horton St., Emeryville, CA 94608. Phone: 510-923-2964; Fax: 510-923-2586; E-mail: Nicholas_Valiante{at}Chiron.com

Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a "control switch" for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF- in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.

Key Words: NK cells • DCs • innate immunity • cytokines • CD86

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• Terme, M., Tomasello, E., Maruyama, K., Crepineau, F., Chaput, N., Flament, C., Marolleau, J.-P., Angevin, E., Wagner, E. F., Salomon, B., Lemonnier, F. A., Wakasugi, H., Colonna, M., Vivier, E., Zitvogel, L. (2004). IL-4 Confers NK Stimulatory Capacity to Murine Dendritic Cells: A Signaling Pathway Involving KARAP/DAP12-Triggering Receptor Expressed on Myeloid Cell 2 Molecules. J. Immunol. 172: 5957-5966 [Abstract] [Full Text]  
• Lee, K.-M., McNerney, M. E., Stepp, S. E., Mathew, P. A., Schatzle, J. D., Bennett, M., Kumar, V. (2004). 2B4 Acts As a Non-Major Histocompatibility Complex Binding Inhibitory Receptor on Mouse Natural Killer Cells. JEM 199: 1245-1254 [Abstract] [Full Text]  
• Tosi, D., Valenti, R., Cova, A., Sovena, G., Huber, V., Pilla, L., Arienti, F., Belardelli, F., Parmiani, G., Rivoltini, L. (2004). Role of Cross-Talk between IFN-{alpha}-Induced Monocyte-Derived Dendritic Cells and NK Cells in Priming CD8+ T Cell Responses against Human Tumor Antigens. J. Immunol. 172: 5363-5370 [Abstract] [Full Text]  
• Ribas, A., Wargo, J. A., Comin-Anduix, B., Sanetti, S., Schumacher, L. Y., McLean, C., Dissette, V. B., Glaspy, J. A., McBride, W. H., Butterfield, L. H., Economou, J. S. (2004). Enhanced Tumor Responses to Dendritic Cells in the Absence of CD8-Positive Cells. J. Immunol. 172: 4762-4769 [Abstract] [Full Text]  
• Pan, P.-Y., Gu, P., Li, Q., Xu, D., Weber, K., Chen, S.-H. (2004). Regulation of Dendritic Cell Function by NK Cells: Mechanisms Underlying the Synergism in the Combination Therapy of IL-12 and 4-1BB Activation. J. Immunol. 172: 4779-4789 [Abstract] [Full Text]  
• Massa, C., Guiducci, C., Arioli, I., Parenza, M., Colombo, M. P., Melani, C. (2004). Enhanced Efficacy of Tumor Cell Vaccines Transfected with Secretable hsp70. Cancer Res. 64: 1502-1508 [Abstract] [Full Text]  
• Li, Q., Pan, P.-Y., Gu, P., Xu, D., Chen, S.-H. (2004). Role of Immature Myeloid Gr-1+ Cells in the Development of Antitumor Immunity. Cancer Res. 64: 1130-1139 [Abstract] [Full Text]  
• Ferlazzo, G., Munz, C. (2004). NK Cell Compartments and Their Activation by Dendritic Cells. J. Immunol. 172: 1333-1339 [Full Text]  
• Ferlazzo, G., Thomas, D., Lin, S.-L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C. (2004). The Abundant NK Cells in Human Secondary Lymphoid Tissues Require Activation to Express Killer Cell Ig-Like Receptors and Become Cytolytic. J. Immunol. 172: 1455-1462 [Abstract] [Full Text]  
• Hayakawa, Y., Screpanti, V., Yagita, H., Grandien, A., Ljunggren, H.-G., Smyth, M. J., Chambers, B. J. (2004). NK Cell TRAIL Eliminates Immature Dendritic Cells In Vivo and Limits Dendritic Cell Vaccination Efficacy. J. Immunol. 172: 123-129 [Abstract] [Full Text]  
• Mailliard, R. B., Son, Y.-I., Redlinger, R., Coates, P. T., Giermasz, A., Morel, P. A., Storkus, W. J., Kalinski, P. (2003). Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function. J. Immunol. 171: 2366-2373 [Abstract] [Full Text]  
• Jin, Y., Knudsen, E., Wang, L., Bryceson, Y., Damaj, B., Gessani, S., Maghazachi, A. A. (2003). Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood 101: 4909-4915 [Abstract] [Full Text]  
• Fehniger, T. A., Cooper, M. A., Nuovo, G. J., Cella, M., Facchetti, F., Colonna, M., Caligiuri, M. A. (2003). CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101: 3052-3057 [Abstract] [Full Text]  
• Castriconi, R., Cantoni, C., Della Chiesa, M., Vitale, M., Marcenaro, E., Conte, R., Biassoni, R., Bottino, C., Moretta, L., Moretta, A. (2003). Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells. Proc. Natl. Acad. Sci. USA 100: 4120-4125 [Abstract] [Full Text]  

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