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The Carlos and Marguerite Mason Transplantation Biology Research Center and Department of Surgery and
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
4 M.A. DeBenedette, T. Wen, M.F. Bochmann, P.S. Ohashi, B.H. Barber, K.L. Stocking, J.J. Pechon, and T.R. Watts. Submitted for publication.
4-1BB (CD137) is a costimulatory molecule expressed on activated T cells and interacts with 4-1BB ligand (4-1BBL) on APCs. To investigate the role of 4-1BB costimulation for the development of primary immune responses, 4-1BBL-deficient (4-1BBL-/-) mice were infected with lymphocytic choriomeningitis virus (LCMV). 4-1BBL-/- mice were able to generate CTL and eliminate acute LCMV infection with normal kinetics, but CD8 T cell expansion was 2- to 3-fold lower than in wild-type (+/+) mice. In the same mice, virus-specific CD4 Th and B cell responses were minimally affected, indicating that 4-1BB costimulation preferentially affects CD8 T cell responses. This result contrasts with our earlier work with CD40L-deficient (CD40L-/-) mice, in which the CD8 T cell response was unaffected and the CD4 T cell response was markedly impaired. When both 4-1BBL- and B7-dependent signals were absent, CD8 T cell expansion was further reduced, resulting in lower CTL activity and impairing their ability to clear LCMV. Altogether, these results indicate that T cells have distinct costimulatory requirements: optimal CD8 responses require 4-1BBL-dependent interactions, whereas CD4 responses are minimally affected by 4-1BB costimulation, but require CD40-CD40L and B7-dependent interactions.
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E. M. Bertram, P. Lau, and T. H. Watts Temporal Segregation of 4-1BB Versus CD28-Mediated Costimulation: 4-1BB Ligand Influences T Cell Numbers Late in the Primary Response and Regulates the Size of the T Cell Memory Response Following Influenza Infection J. Immunol., April 15, 2002; 168(8): 3777 - 3785. [Abstract] [Full Text] [PDF]
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M. Suresh, J. K. Whitmire, L. E. Harrington, C. P. Larsen, T. C. Pearson, J. D. Altman, and R. Ahmed Role of CD28-B7 Interactions in Generation and Maintenance of CD8 T Cell Memory J. Immunol., November 15, 2001; 167(10): 5565 - 5573. [Abstract] [Full Text] [PDF]
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M. Prlic, B. R. Blazar, A. Khoruts, T. Zell, and S. C. Jameson Homeostatic Expansion Occurs Independently of Costimulatory Signals J. Immunol., November 15, 2001; 167(10): 5664 - 5668. [Abstract] [Full Text] [PDF]
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K. Nozawa, J. Ohata, J. Sakurai, H. Hashimoto, H. Miyajima, H. Yagita, K. Okumura, and M. Azuma 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., November 1, 2001; 167(9): 4981 - 4986. [Abstract] [Full Text] [PDF]
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G. Zhu, D. B. Flies, K. Tamada, Y. Sun, M. Rodriguez, Y.-X. Fu, and L. Chen Progressive Depletion of Peripheral B Lymphocytes in 4-1BB (CD137) Ligand/I-E{alpha}-Transgenic Mice J. Immunol., September 1, 2001; 167(5): 2671 - 2676. [Abstract] [Full Text] [PDF]
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J. L. Cannons, P. Lau, B. Ghumman, M. A. DeBenedette, H. Yagita, K. Okumura, and T. H. Watts 4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy J. Immunol., August 1, 2001; 167(3): 1313 - 1324. [Abstract] [Full Text] [PDF]
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B. R. Blazar, B. S. Kwon, A. Panoskaltsis-Mortari, K. B. Kwak, J. J. Peschon, and P. A. Taylor Ligation of 4-1BB (CDw137) Regulates Graft-Versus-Host Disease, Graft-Versus-Leukemia, and Graft Rejection in Allogeneic Bone Marrow Transplant Recipients J. Immunol., March 1, 2001; 166(5): 3174 - 3183. [Abstract] [Full Text] [PDF]
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K. H. Edelmann and C. B. Wilson Role of CD28/CD80-86 and CD40/CD154 Costimulatory Interactions in Host Defense to Primary Herpes Simplex Virus Infection J. Virol., January 15, 2001; 75(2): 612 - 621. [Abstract] [Full Text]
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