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*
Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
A costimulatory member of the TNFR family, 4-1BB, is expressed on
activated T cells. Although some reports have suggested that 4-1BB is
primarily involved in CD8 T cell activation, in this report we
demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand
(4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells
up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated
costimulation during a primary response to peptide Ag. 4-1BBL enhanced
proliferation, cytokine production, and CTL effector function of TCR
transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under
similar conditions of antigenic stimulation, we performed MLRs with
purified CD4 or CD8 responders from CD28+/+ and
CD28-/- mice. We found that CD8 T cells produced IL-2 and
IFN-
in a 4-1BBL-dependent manner, whereas under the same conditions
the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4
and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T
cells both responded to anti-CD3 plus s4-1BBL with a similar
cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited
enhanced proliferation and earlier cell division when stimulated with
anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL,
and both subsets responded comparably to anti-CD3 plus 4-1BBL.
These data support the idea that CD28 plays a primary role in initial T
cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell
responses, as well as enhances cell division and T cell effector
function.
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R. Carrio, O. F. Bathe, and T. R. Malek Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment J. Immunol., June 15, 2004; 172(12): 7315 - 7323. [Abstract] [Full Text] [PDF]
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S. K. Lathrop, C. A. Huddleston, P. A. Dullforce, M. J. Montfort, A. D. Weinberg, and D. C. Parker A Signal through OX40 (CD134) Allows Anergic, Autoreactive T Cells to Acquire Effector Cell Functions J. Immunol., June 1, 2004; 172(11): 6735 - 6743. [Abstract] [Full Text] [PDF]
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B. K. Choi, J. S. Bae, E. M. Choi, W. J. Kang, S. Sakaguchi, D. S. Vinay, and B. S. Kwon 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells J. Leukoc. Biol., May 1, 2004; 75(5): 785 - 791. [Abstract] [Full Text] [PDF]
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K. Saito, N. Ohara, H. Hotokezaka, S. Fukumoto, K. Yuasa, M. Naito, T. Fujiwara, and K. Nakayama Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/RANKL-induced in Vitro Osteoclastogenesis J. Biol. Chem., April 2, 2004; 279(14): 13555 - 13563. [Abstract] [Full Text] [PDF]
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J. Bukczynski, T. Wen, K. Ellefsen, J. Gauldie, and T. H. Watts Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses PNAS, February 3, 2004; 101(5): 1291 - 1296. [Abstract] [Full Text] [PDF]
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G. Demirci, F. Amanullah, R. Kewalaramani, H. Yagita, T. B. Strom, M. H. Sayegh, and X. C. Li Critical Role of OX40 in CD28 and CD154-Independent Rejection J. Immunol., February 1, 2004; 172(3): 1691 - 1698. [Abstract] [Full Text] [PDF]
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E. M. Bertram, W. Dawicki, B. Sedgmen, J. L. Bramson, D. H. Lynch, and T. H. Watts A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo J. Immunol., January 15, 2004; 172(2): 981 - 988. [Abstract] [Full Text] [PDF]
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R. A. Wilcox, K. Tamada, D. B. Flies, G. Zhu, A. I. Chapoval, B. R. Blazar, W. M. Kast, and L. Chen Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo Blood, January 1, 2004; 103(1): 177 - 184. [Abstract] [Full Text] [PDF]
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R. A. Wilcox, D. B. Flies, H. Wang, K. Tamada, A. J. Johnson, L. R. Pease, M. Rodriguez, Y. Guo, and L. Chen Impaired Infiltration of Tumor-specific Cytolytic T Cells in the Absence of Interferon-{gamma} despite Their Normal Maturation in Lymphoid Organs during CD137 Monoclonal Antibody Therapy Cancer Res., August 1, 2002; 62(15): 4413 - 4418. [Abstract] [Full Text] [PDF]
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 J. M. Tarrant, J. Groom, D. Metcalf, R. Li, B. Borobokas, M. D. Wright, D. Tarlinton, and L. Robb The Absence of Tssc6, a Member of the Tetraspanin Superfamily, Does Not Affect Lymphoid Development but Enhances In Vitro T-Cell Proliferative Responses Mol. Cell. Biol., July 15, 2002; 22(14): 5006 - 5018. [Abstract] [Full Text] [PDF]
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D. Cappellen, N.-H. Luong-Nguyen, S. Bongiovanni, O. Grenet, C. Wanke, and M. Susa Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFkappa B J. Biol. Chem., June 7, 2002; 277(24): 21971 - 21982. [Abstract] [Full Text] [PDF]
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K. F. May Jr., L. Chen, P. Zheng, and Y. Liu Anti-4-1BB Monoclonal Antibody Enhances Rejection of Large Tumor Burden by Promoting Survival but not Clonal Expansion of Tumor-specific CD8+ T Cells Cancer Res., June 1, 2002; 62(12): 3459 - 3465. [Abstract] [Full Text] [PDF]
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T. Wen, J. Bukczynski, and T. H. Watts 4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function J. Immunol., May 15, 2002; 168(10): 4897 - 4906. [Abstract] [Full Text] [PDF]
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R. A. Wilcox, A. I. Chapoval, K. S. Gorski, M. Otsuji, T. Shin, D. B. Flies, K. Tamada, R. S. Mittler, H. Tsuchiya, D. M. Pardoll, et al. Expression of Functional CD137 Receptor by Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4262 - 4267. [Abstract] [Full Text] [PDF]
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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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 A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [Full Text] [PDF]
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Y. Sun, X. Lin, H. M. Chen, Q. Wu, S. K. Subudhi, L. Chen, and Y.-X. Fu Administration of Agonistic Anti-4-1BB Monoclonal Antibody Leads to the Amelioration of Experimental Autoimmune Encephalomyelitis J. Immunol., February 1, 2002; 168(3): 1457 - 1465. [Abstract] [Full Text] [PDF]
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S. E. Hamilton, A. R. Tvinnereim, and J. T. Harty Listeria monocytogenes Infection Overcomes the Requirement for CD40 Ligand in Exogenous Antigen Presentation to CD8+ T Cells J. Immunol., November 15, 2001; 167(10): 5603 - 5609. [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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G. J. D. van Mierlo, A. Th. den Boer, J. P. Medema, E. I. H. van der Voort, M. F. Fransen, R. Offringa, C. J. M. Melief, and R. E. M. Toes CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity PNAS, April 16, 2002; 99(8): 5561 - 5566. [Abstract] [Full Text] [PDF]
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