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*
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and
Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213
Ox-40 and Ox-40 ligand (Ox-40L) are thought to be involved in T cell-APC interactions. However, their exact role in T cell responses is undefined. Using fibroblast transfectants expressing Ox-40L and/or B7-1, and CD4 cells from TCR transgenic mice, we investigated the effect of Ox-40 signaling on primary responses to the Ag pigeon cytochrome c. Ox-40 expression on naive CD4 cells peaked 2 to 3 days after activation, and was lost by 4 to 5 days. APCs with Ox-40L promoted partial activation of naive T cells with some IL-2 secretion, but were unable to enhance proliferation, unlike those with B7-1. APCs coexpressing Ox-40L with B7-1 induced large quantities of IL-2 and promoted proliferative responses that persisted for several days. Effector cells taken 5 days after naive T cell activation reexpressed Ox-40 within 4 h and responded strongly to APCs expressing Ox-40L, whereas B7-1 had little effect. Synergy was also seen between Ox-40L and B7-1, with primarily IL-2 being elevated, although IL-4 and IL-5 were also up-regulated. The most striking action was on effector T cell proliferation, which continued at high levels for up to 4 days, with little proliferation evident at this time in the absence of Ox-40 signals. These data suggest that Ox-40/Ox-40L interactions act after initial activation events to prolong clonal expansion and enhance effector cytokine secretion, and may be involved in promoting long-lived primary CD4 responses.
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B. R. Blazar, A. H. Sharpe, A. I. Chen, A. Panoskaltsis-Mortari, C. Lees, H. Akiba, H. Yagita, N. Killeen, and P. A. Taylor Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients Blood, May 1, 2003; 101(9): 3741 - 3748. [Abstract] [Full Text] [PDF]
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X. Yuan, A. D. Salama, V. Dong, I. Schmitt, N. Najafian, A. Chandraker, H. Akiba, H. Yagita, and M. H. Sayegh The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo J. Immunol., March 15, 2003; 170(6): 2949 - 2955. [Abstract] [Full Text] [PDF]
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M. J. Ekkens, Z. Liu, Q. Liu, J. Whitmire, S. Xiao, A. Foster, J. Pesce, J. VanNoy, A. H. Sharpe, J. F. Urban, et al. The Role of OX40 Ligand Interactions in the Development of the Th2 Response to the Gastrointestinal Nematode Parasite Heligmosomoides polygyrus J. Immunol., January 1, 2003; 170(1): 384 - 393. [Abstract] [Full Text] [PDF]
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J. L. Cannons, E. M. Bertram, and T. H. Watts Cutting Edge: Profound Defect in T Cell Responses in TNF Receptor-Associated Factor 2 Dominant Negative Mice J. Immunol., September 15, 2002; 169(6): 2828 - 2831. [Abstract] [Full Text] [PDF]
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S. Ronchetti, G. Nocentini, C. Riccardi, and P. P. Pandolfi Role of GITR in activation response of T lymphocytes Blood, June 17, 2002; 100(1): 350 - 352. [Abstract] [Full Text] [PDF]
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C. Chirathaworn, J. E. Kohlmeier, S. A. Tibbetts, L. M. Rumsey, M. A. Chan, and S. H. Benedict Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation J. Immunol., June 1, 2002; 168(11): 5530 - 5537. [Abstract] [Full Text] [PDF]
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W. Ise, M. Totsuka, Y. Sogawa, A. Ametani, S. Hachimura, T. Sato, Y. Kumagai, S. Habu, and S. Kaminogawa Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen J. Immunol., April 1, 2002; 168(7): 3242 - 3250. [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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T. De Smedt, J. Smith, P. Baum, W. Fanslow, E. Butz, and C. Maliszewski Ox40 Costimulation Enhances the Development of T Cell Responses Induced by Dendritic Cells In Vivo J. Immunol., January 15, 2002; 168(2): 661 - 670. [Abstract] [Full Text] [PDF]
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H.-C. Wang and J. R. Klein Multiple Levels of Activation of Murine CD8+ Intraepithelial Lymphocytes Defined by OX40 (CD134) Expression: Effects on Cell-Mediated Cytotoxicity, IFN-{gamma}, and IL-10 Regulation J. Immunol., December 15, 2001; 167(12): 6717 - 6723. [Abstract] [Full Text] [PDF]
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D. E. Evans, R. A. Prell, C. J. Thalhofer, A. A. Hurwitz, and A. D. Weinberg Engagement of OX40 Enhances Antigen-Specific CD4+ T Cell Mobilization/Memory Development and Humoral Immunity: Comparison of {alpha}OX-40 with {alpha}CTLA-4 J. Immunol., December 15, 2001; 167(12): 6804 - 6811. [Abstract] [Full Text] [PDF]
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M. Kelleher and P. C. L. Beverley 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., December 1, 2001; 167(11): 6247 - 6255. [Abstract] [Full Text] [PDF]
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L. C. Ndhlovu, N. Ishii, K. Murata, T. Sato, and K. Sugamura Critical Involvement of OX40 Ligand Signals in the T Cell Priming Events During Experimental Autoimmune Encephalomyelitis J. Immunol., September 1, 2001; 167(5): 2991 - 2999. [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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S. Nakae, M. Asano, R. Horai, N. Sakaguchi, and Y. Iwakura IL-1 Enhances T Cell-Dependent Antibody Production Through Induction of CD40 Ligand and OX40 on T Cells J. Immunol., July 1, 2001; 167(1): 90 - 97. [Abstract] [Full Text] [PDF]
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V. Malmstrom, D. Shipton, B. Singh, A. Al-Shamkhani, M. J. Puklavec, A. N. Barclay, and F. Powrie CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice J. Immunol., June 1, 2001; 166(11): 6972 - 6981. [Abstract] [Full Text] [PDF]
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A. G.-H. Jember, R. Zuberi, F.-T. Liu, and M. Croft Development of Allergic Inflammation in a Murine Model of Asthma Is Dependent on the Costimulatory Receptor Ox40 J. Exp. Med., February 5, 2001; 193(3): 387 - 392. [Abstract] [Full Text] [PDF]
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C. Nohara, H. Akiba, A. Nakajima, A. Inoue, C.-S. Koh, H. Ohshima, H. Yagita, Y. Mizuno, and K. Okumura Amelioration of Experimental Autoimmune Encephalomyelitis with Anti-OX40 Ligand Monoclonal Antibody: A Critical Role for OX40 Ligand in Migration, But Not Development, of Pathogenic T Cells J. Immunol., February 1, 2001; 166(3): 2108 - 2115. [Abstract] [Full Text] [PDF]
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J. Kjærgaard, J. Tanaka, J. A. Kim, K. Rothchild, A. Weinberg, and S. Shu Therapeutic Efficacy of OX-40 Receptor Antibody Depends on Tumor Immunogenicity and Anatomic Site of Tumor Growth Cancer Res., October 1, 2000; 60(19): 5514 - 5521. [Abstract] [Full Text]
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I. Gramaglia, A. Jember, S. D. Pippig, A. D. Weinberg, N. Killeen, and M. Croft The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion J. Immunol., September 15, 2000; 165(6): 3043 - 3050. [Abstract] [Full Text] [PDF]
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J. ATEN, A. ROOS, N. CLAESSEN, E. J. M. SCHILDER-TOL, I. J. M. TEN BERGE, and J. J. WEENING Strong and Selective Glomerular Localization of CD134 Ligand and TNF Receptor-1 in Proliferative Lupus Nephritis J. Am. Soc. Nephrol., August 1, 2000; 11(8): 1426 - 1438. [Abstract] [Full Text]
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R. Pankow, H. Durkop, U. Latza, H. Krause, U. Kunzendorf, T. Pohl, and S. Bulfone-Paus The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression J. Immunol., July 1, 2000; 165(1): 263 - 270. [Abstract] [Full Text] [PDF]
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P. R. Rogers and M. Croft CD28, Ox-40, LFA-1, and CD4 Modulation of Th1/Th2 Differentiation Is Directly Dependent on the Dose of Antigen J. Immunol., March 15, 2000; 164(6): 2955 - 2963. [Abstract] [Full Text] [PDF]
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A. D. Weinberg, M.-M. Rivera, R. Prell, A. Morris, T. Ramstad, J. T. Vetto, W. J. Urba, G. Alvord, C. Bunce, and J. Shields Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity J. Immunol., February 15, 2000; 164(4): 2160 - 2169. [Abstract] [Full Text] [PDF]
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K. Murata, N. Ishii, H. Takano, S. Miura, L. C. Ndhlovu, M. Nose, T. Noda, and K. Sugamura Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand J. Exp. Med., January 17, 2000; 191(2): 365 - 374. [Abstract] [Full Text] [PDF]
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P. Lane Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells J. Exp. Med., January 17, 2000; 191(2): 201 - 206. [Full Text] [PDF]
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J. R. Maxwell, A. Weinberg, R. A. Prell, and A. T. Vella Danger and OX40 Receptor Signaling Synergize to Enhance Memory T Cell Survival by Inhibiting Peripheral Deletion J. Immunol., January 1, 2000; 164(1): 107 - 112. [Abstract] [Full Text] [PDF]
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S. D. Pippig, C. Pena-Rossi, J. Long, W. R. Godfrey, D. J. Fowell, S. L. Reiner, M. L. Birkeland, R. M. Locksley, A. N. Barclay, and N. Killeen Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40) J. Immunol., December 15, 1999; 163(12): 6520 - 6529. [Abstract] [Full Text] [PDF]
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L. S.K. Walker, A. Gulbranson-Judge, S. Flynn, T. Brocker, C. Raykundalia, M. Goodall, R. Forster, M. Lipp, and P. Lane Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5-Positive Cd4 Cells and Germinal Centers J. Exp. Med., October 18, 1999; 190(8): 1115 - 1122. [Abstract] [Full Text] [PDF]
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J. L. Cannons, K. P. Hoeflich, J. R. Woodgett, and T. H. Watts Role of the Stress Kinase Pathway in Signaling Via the T Cell Costimulatory Receptor 4-1BB J. Immunol., September 15, 1999; 163(6): 2990 - 2998. [Abstract] [Full Text] [PDF]
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A. D. Weinberg, K. W. Wegmann3, C. Funatake, and R. H. Whitham Blocking OX-40/OX-40 Ligand Interaction In Vitro and In Vivo Leads to Decreased T Cell Function and Amelioration of Experimental Allergic Encephalomyelitis J. Immunol., February 1, 1999; 162(3): 1818 - 1826. [Abstract] [Full Text] [PDF]
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M. Gerloni, S. Xiong, S. Mukerjee, S. P. Schoenberger, M. Croft, and M. Zanetti From the Cover: Functional cooperation between T helper cell determinants PNAS, November 21, 2000; 97(24): 13269 - 13274. [Abstract] [Full Text] [PDF]
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