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*
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121;
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; and
Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213
The costimulatory receptor OX40 has recently been shown to be involved in primary CD4 responses to several defined Ags. However, to date there has been little information regarding the mechanism of action of OX40, such as whether it regulates T cell numbers, reactivity, or both, and whether it contributes to induction of long-term T cell responses. With an agonist Ab to OX40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show that ligation of OX40 induces clonal expansion and survival of CD4 cells during primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice generated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter phases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of surviving memory cells. These results demonstrate that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.
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T. So, S. Salek-Ardakani, H. Nakano, C. F. Ware, and M. Croft TNF Receptor-Associated Factor 5 Limits the Induction of Th2 Immune Responses J. Immunol., April 1, 2004; 172(7): 4292 - 4297. [Abstract] [Full Text] [PDF]
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I. Takeda, S. Ine, N. Killeen, L. C. Ndhlovu, K. Murata, S. Satomi, K. Sugamura, and N. Ishii Distinct Roles for the OX40-OX40 Ligand Interaction in Regulatory and Nonregulatory T Cells J. Immunol., March 15, 2004; 172(6): 3580 - 3589. [Abstract] [Full Text] [PDF]
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N. Martin-Orozco, Z. Chen, L. Poirot, E. Hyatt, A. Chen, O. Kanagawa, A. Sharpe, D. Mathis, and C. Benoist Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand J. Immunol., December 15, 2003; 171(12): 6954 - 6960. [Abstract] [Full Text] [PDF]
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R. A. Prell, D. E. Evans, C. Thalhofer, T. Shi, C. Funatake, and A. D. Weinberg OX40-Mediated Memory T Cell Generation Is TNF Receptor-Associated Factor 2 Dependent J. Immunol., December 1, 2003; 171(11): 5997 - 6005. [Abstract] [Full Text] [PDF]
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F. G. Lakkis and M. H. Sayegh Memory T Cells: A Hurdle to Immunologic Tolerance J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2402 - 2410. [Full Text] [PDF]
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I. R. Humphreys, L. Edwards, G. Walzl, A. J. Rae, G. Dougan, S. Hill, and T. Hussell OX40 Ligation on Activated T Cells Enhances the Control of Cryptococcus neoformans and Reduces Pulmonary Eosinophilia J. Immunol., June 15, 2003; 170(12): 6125 - 6132. [Abstract] [Full Text] [PDF]
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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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P.-J. Linton, B. Bautista, E. Biederman, E. S. Bradley, J. Harbertson, R. M. Kondrack, R. C. Padrick, and L. M. Bradley Costimulation via OX40L Expressed by B Cells Is Sufficient to Determine the Extent of Primary CD4 Cell Expansion and Th2 Cytokine Secretion In Vivo J. Exp. Med., April 7, 2003; 197(7): 875 - 883. [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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A. Curti, M. Parenza, and M. P. Colombo Autologous and MHC class I-negative allogeneic tumor cells secreting IL-12 together cure disseminated A20 lymphoma Blood, January 15, 2003; 101(2): 568 - 575. [Abstract] [Full Text] [PDF]
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G. Gri, E. Gallo, E. Di Carlo, P. Musiani, and M. P. Colombo OX40 Ligand-Transduced Tumor Cell Vaccine Synergizes with GM-CSF and Requires CD40-Apc Signaling to Boost the Host T Cell Antitumor Response J. Immunol., January 1, 2003; 170(1): 99 - 106. [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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K. Murata, M. Nose, L. C. Ndhlovu, T. Sato, K. Sugamura, and N. Ishii Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases J. Immunol., October 15, 2002; 169(8): 4628 - 4636. [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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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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J. Kjaergaard, L. Peng, P. A. Cohen, J. A. Drazba, A. D. Weinberg, and S. Shu Augmentation Versus Inhibition: Effects of Conjunctional OX-40 Receptor Monoclonal Antibody and IL-2 Treatment on Adoptive Immunotherapy of Advanced Tumor J. Immunol., December 1, 2001; 167(11): 6669 - 6677. [Abstract] [Full Text] [PDF]
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J. Mestas and C. C. W. Hughes Endothelial Cell Costimulation of T Cell Activation Through CD58-CD2 Interactions Involves Lipid Raft Aggregation J. Immunol., October 15, 2001; 167(8): 4378 - 4385. [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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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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 M. Gerloni, S. Xiong, S. Mukerjee, S. P. Schoenberger, M. Croft, and M. Zanetti Functional cooperation between T helper cell determinants PNAS, November 2, 2000; (2000) 230429197. [Abstract] [Full Text]
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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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