J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/07/47/09 $2.00
Volume 186, Number 1, July 7, 1997 47-55

4-1BB Costimulatory Signals Preferentially Induce CD8⁺ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses

By Walter W. Shuford,^* Kerry Klussman,^* Douglas D. Tritchler,^* Deryk T. Loo,^* Jan Chalupny,^* Anthony W. Siadak,^* T. Joseph Brown,^* John Emswiler,^* Hong Raecho, Christian P. Larsen, Thomas C. Pearson, Jeffrey A. Ledbetter,^* Alejandro Aruffo,^* and Robert S. Mittler^*

From the ^* Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121; and  Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322

The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4⁺ and CD8⁺ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8⁺ T cells when compared with CD4⁺ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2^d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4⁺ and CD8⁺ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon- production by CD8⁺ T cells and that anti-4-1BB mediated proliferation of CD8⁺ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

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• Yamada, A., Salama, A. D., Sayegh, M. H. (2002). The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation. J. Am. Soc. Nephrol. 13: 559-575 [Full Text]  
• Sun, Y., Lin, X., Chen, H. M., Wu, Q., Subudhi, S. K., Chen, L., Fu, Y.-X. (2002). Administration of Agonistic Anti-4-1BB Monoclonal Antibody Leads to the Amelioration of Experimental Autoimmune Encephalomyelitis. J. Immunol. 168: 1457-1465 [Abstract] [Full Text]  
• Kelleher, M., Beverley, P. C. L. (2001). Lipopolysaccharide Modulation of Dendritic Cells Is Insufficient to Mature Dendritic Cells to Generate CTLs from Naive Polyclonal CD8+ T Cells In Vitro, Whereas CD40 Ligation Is Essential. J. Immunol. 167: 6247-6255 [Abstract] [Full Text]  
• Zheng, G., Chen, A., Sterner, R. E., Zhang, P. J., Pan, T., Kiyatkin, N., Tykocinski, M. L. (2001). Induction of Antitumor Immunity via Intratumoral Tetra-Costimulator Protein Transfer. Cancer Res. 61: 8127-8134 [Abstract] [Full Text]  
• Nozawa, K., Ohata, J., Sakurai, J., Hashimoto, H., Miyajima, H., Yagita, H., Okumura, K., Azuma, M. (2001). Preferential Blockade of CD8+ T Cell Responses by Administration of Anti-CD137 Ligand Monoclonal Antibody Results in Differential Effect on Development of Murine Acute and Chronic Graft-Versus-Host Diseases. J. Immunol. 167: 4981-4986 [Abstract] [Full Text]  
• Zhu, G., Flies, D. B., Tamada, K., Sun, Y., Rodriguez, M., Fu, Y.-X., Chen, L. (2001). Progressive Depletion of Peripheral B Lymphocytes in 4-1BB (CD137) Ligand/I-E{alpha}-Transgenic Mice. J. Immunol. 167: 2671-2676 [Abstract] [Full Text]  
• Cannons, J. L., Lau, P., Ghumman, B., DeBenedette, M. A., Yagita, H., Okumura, K., Watts, T. H. (2001). 4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy. J. Immunol. 167: 1313-1324 [Abstract] [Full Text]  
• Kim, J. A., Averbook, B. J., Chambers, K., Rothchild, K., Kjaergaard, J., Papay, R., Shu, S. (2001). Divergent Effects of 4-1BB Antibodies on Antitumor Immunity and on Tumor-reactive T-Cell Generation. Cancer Res. 61: 2031-2037 [Abstract] [Full Text]  
• Blazar, B. R., Kwon, B. S., Panoskaltsis-Mortari, A., Kwak, K. B., Peschon, J. J., Taylor, P. A. (2001). Ligation of 4-1BB (CDw137) Regulates Graft-Versus-Host Disease, Graft-Versus-Leukemia, and Graft Rejection in Allogeneic Bone Marrow Transplant Recipients. J. Immunol. 166: 3174-3183 [Abstract] [Full Text]  
• Edelmann, K. H., Wilson, C. B. (2001). Role of CD28/CD80-86 and CD40/CD154 Costimulatory Interactions in Host Defense to Primary Herpes Simplex Virus Infection. J. Virol. 75: 612-621 [Abstract] [Full Text]  
• Broeren, C. P. M., Gray, G. S., Carreno, B. M., June, C. H. (2000). Costimulation Light: Activation of CD4+ T Cells with CD80 or CD86 Rather Than Anti-CD28 Leads to a Th2 Cytokine Profile. J. Immunol. 165: 6908-6914 [Abstract] [Full Text]  
• Cannons, J. L., Choi, Y., Watts, T. H. (2000). Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response. J. Immunol. 165: 6193-6204 [Abstract] [Full Text]  
• Blazar, B. R., Lees, C. J., Martin, P. J., Noelle, R. J., Kwon, B., Murphy, W., Taylor, P. A. (2000). Host T Cells Resist Graft-Versus-Host Disease Mediated by Donor Leukocyte Infusions. J. Immunol. 165: 4901-4909 [Abstract] [Full Text]  
• Lanzavecchia, A., Sallusto, F. (2000). Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells. Science 290: 92-97 [Abstract] [Full Text]  
• Kjærgaard, J., Tanaka, J., Kim, J. A., Rothchild, K., Weinberg, A., Shu, S. (2000). Therapeutic Efficacy of OX-40 Receptor Antibody Depends on Tumor Immunogenicity and Anatomic Site of Tumor Growth. Cancer Res. 60: 5514-5521 [Abstract] [Full Text]  
• Kornbluth, R. S. (2000). The emerging role of CD40 ligand in HIV infection. J. Leukoc. Biol. 68: 373-382 [Abstract] [Full Text]  
• Salih, H. R., Kosowski, S. G., Haluska, V. F., Starling, G. C., Loo, D. T., Lee, F., Aruffo, A. A., Trail, P. A., Kiener, P. A. (2000). Constitutive Expression of Functional 4-1BB (CD137) Ligand on Carcinoma Cells. J. Immunol. 165: 2903-2910 [Abstract] [Full Text]  
• Martinet, O., Ermekova, V., Qiao, J. Q., Sauter, B., Mandeli, J., Chen, L., Chen, S.-H. (2000). Immunomodulatory Gene Therapy With Interleukin 12 and 4-1BB Ligand: Long- Term Remission of Liver Metastases in a Mouse Model. JNCI J Natl Cancer Inst 92: 931-936 [Abstract] [Full Text]  
• Tamada, K., Shimozaki, K., Chapoval, A. I., Zhai, Y., Su, J., Chen, S.-F., Hsieh, S.-L., Nagata, S., Ni, J., Chen, L. (2000). LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response. J. Immunol. 164: 4105-4110 [Abstract] [Full Text]  

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