Brief Definitive Report

Antigen-specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells

Correspondence to: Madhav V. Dhodapkar, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Ave. #176, New York, NY 10021. Tel:212-327-8110 Fax:212-327-8875 E-mail:dhodapm{at}rockvax.rockefeller.edu.

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4⁺ and CD8⁺ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8⁺ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10–producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.

Key Words: dendritic cells, maturation, tolerance, CD8⁺ T cells, immunization

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• Herring, A. C., Falkowski, N. R., Chen, G.-H., McDonald, R. A., Toews, G. B., Huffnagle, G. B. (2005). Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells. Infect. Immun. 73: 39-49 [Abstract] [Full Text]  
• Bonnotte, B., Crittenden, M., Larmonier, N., Gough, M., Vile, R. G. (2004). MIP-3{alpha} Transfection into a Rodent Tumor Cell Line Increases Intratumoral Dendritic Cell Infiltration but Enhances (Facilitates) Tumor Growth and Decreases Immunogenicity. J. Immunol. 173: 4929-4935 [Abstract] [Full Text]  
• O'Neill, D. W., Adams, S., Bhardwaj, N. (2004). Manipulating dendritic cell biology for the active immunotherapy of cancer. Blood 104: 2235-2246 [Abstract] [Full Text]  
• Haase, C., Skak, K., Michelsen, B. K., Markholst, H. (2004). Local Activation of Dendritic Cells Leads to Insulitis and Development of Insulin-Dependent Diabetes in Transgenic Mice Expressing CD154 on the Pancreatic {beta}-Cells. Diabetes 53: 2588-2595 [Abstract] [Full Text]  
• Moseman, E. A., Liang, X., Dawson, A. J., Panoskaltsis-Mortari, A., Krieg, A. M., Liu, Y.-J., Blazar, B. R., Chen, W. (2004). Human Plasmacytoid Dendritic Cells Activated by CpG Oligodeoxynucleotides Induce the Generation of CD4+CD25+ Regulatory T Cells. J. Immunol. 173: 4433-4442 [Abstract] [Full Text]  
• Adams, S., O'Neill, D., Bhardwaj, N. (2004). Maturation Matters: Importance of Maturation for Antitumor Immunity of Dendritic Cell Vaccines. JCO 22: 3834-3835 [Full Text]  
• Park, S.-J., Nakagawa, T., Kitamura, H., Atsumi, T., Kamon, H., Sawa, S.-i., Kamimura, D., Ueda, N., Iwakura, Y., Ishihara, K., Murakami, M., Hirano, T. (2004). IL-6 Regulates In Vivo Dendritic Cell Differentiation through STAT3 Activation. J. Immunol. 173: 3844-3854 [Abstract] [Full Text]  
• Mailliard, R. B., Wankowicz-Kalinska, A., Cai, Q., Wesa, A., Hilkens, C. M., Kapsenberg, M. L., Kirkwood, J. M., Storkus, W. J., Kalinski, P. (2004). {alpha}-Type-1 Polarized Dendritic Cells: A Novel Immunization Tool with Optimized CTL-inducing Activity. Cancer Res. 64: 5934-5937 [Abstract] [Full Text]  
• Epardaud, M., Bonneau, M., Payot, F., Cordier, C., Megret, J., Howard, C., Schwartz-Cornil, I. (2004). Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero-digestive tract. J. Leukoc. Biol. 76: 553-561 [Abstract] [Full Text]  
• Chen, X., Doffek, K., Sugg, S. L., Shilyansky, J. (2004). Phosphatidylserine Regulates the Maturation of Human Dendritic Cells. J. Immunol. 173: 2985-2994 [Abstract] [Full Text]  
• Cignetti, A., Vallario, A., Roato, I., Circosta, P., Allione, B., Casorzo, L., Ghia, P., Caligaris-Cappio, F. (2004). Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses. J. Immunol. 173: 2855-2865 [Abstract] [Full Text]  
• Avigan, D., Vasir, B., Gong, J., Borges, V., Wu, Z., Uhl, L., Atkins, M., Mier, J., McDermott, D., Smith, T., Giallambardo, N., Stone, C., Schadt, K., Dolgoff, J., Tetreault, J.-C., Villarroel, M., Kufe, D. (2004). Fusion Cell Vaccination of Patients with Metastatic Breast and Renal Cancer Induces Immunological and Clinical Responses. Clin. Cancer Res. 10: 4699-4708 [Abstract] [Full Text]  
• Nencioni, A., Brossart, P. (2004). Cellular Immunotherapy with Dendritic Cells in Cancer: Current Status. Stem Cells 22: 501-513 [Abstract] [Full Text]  
• Vigouroux, S., Yvon, E., Biagi, E., Brenner, M. K. (2004). Antigen-induced regulatory T cells. Blood 104: 26-33 [Abstract] [Full Text]  
• Larsson, M., Babcock, E., Grakoui, A., Shoukry, N., Lauer, G., Rice, C., Walker, C., Bhardwaj, N. (2004). Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus. J. Virol. 78: 6151-6161 [Abstract] [Full Text]  
• Maus, M. V., Kovacs, B., Kwok, W. W., Nepom, G. T., Schlienger, K., Riley, J. L., Allman, D., Finkel, T. H., June, C. H. (2004). Extensive Replicative Capacity of Human Central Memory T Cells. J. Immunol. 172: 6675-6683 [Abstract] [Full Text]  
• Rouas, R., Lewalle, P., El Ouriaghli, F., Nowak, B., Duvillier, H., Martiat, P. (2004). Poly(I:C) used for human dendritic cell maturation preserves their ability to secondarily secrete bioactive IL-12. Int Immunol 16: 767-773 [Abstract] [Full Text]  
• Kan-Mitchell, J., Bisikirska, B., Wong-Staal, F., Schaubert, K. L., Bajcz, M., Bereta, M. (2004). The HIV-1 HLA-A2-SLYNTVATL Is a Help-Independent CTL Epitope. J. Immunol. 172: 5249-5261 [Abstract] [Full Text]  

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