4-1BB Ligand, a Member of the TNF Family, Is Important for the Generation of Antiviral CD8 T Cell Responses

Journal of Immunology - Tập 163 Số 9 - Trang 4859-4868 - 1999
Joyce T. Tan1,2, Jason K. Whitmire2,3, Rafi Ahmed2,3, Thomas C. Pearson1,2, Christian P. Larsen1,2
1*The Carlos and Marguerite Mason Transplantation Biology Research Center and Department of Surgery and
24 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.
3*Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;

Tóm tắt

Abstract4-1BB (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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Tài liệu tham khảo

Koup, R. A., J. T. Safrit, Y. Cao, C. A. Andrews, G. McLeod, W. Borkowsky, C. Farthing, D. D. Ho. 1994. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68: 4650

Pantaleo, G., J. F. Demarest, H. Soudeyns, C. Graziosi, F. Denis, J. W. Adelsberger, P. Borrow, M. S. Saag, G. M. Shaw, R. P. Sekaly, et al 1994. Major expansion of CD8+ T cells with a predominant Vβ usage during the primary immune response to HIV. Nature 370: 463

Pantaleo, G., H. Soudeyns, J. F. Demarest, M. Vaccarezza, C. Graziosi, S. Paolucci, M. Daucher, O. J. Cohen, F. Denis, W. E. Biddison, et al 1997. Evidence for a rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc. Natl. Acad. Sci. USA 94: 9848

Griffin, D. E.. 1995. Immune responses during measles virus infection. Curr. Top. Microbiol. Immunol. 191: 117

Callan, M. F., N. Steven, P. Krausa, J. D. Wilson, P. A. Moss, G. M. Gillespie, J. I. Bell, A. B. Rickinson, A. J. McMichael. 1996. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat. Med. 2: 906

Oldstone, M. B. A.. 1996. Virus-lymphoid cell interactions. Proc. Natl. Acad. Sci. USA 93: 12756

Wills, M. R., A. J. Carmichael, K. Mynard, X. Jin, M. P. Weekes, B. Plachter, J. G. Sissons. 1996. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J. Virol. 70: 7569

Borrow, P., H. Lewicki, X. Wei, M. S. Horwitz, N. Peffer, H. Meyers, J. A. Nelson, J. E. Gairin, B. H. Hahn, M. B. Oldstone, G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3: 205

Steven, N. M., N. E. Annels, A. Kumar, A. M. Leese, M. G. Kurilla, A. B. Rickinson. 1997. Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J. Exp. Med. 185: 1605

Lau, L. L., B. D. Jamieson, T. Somasundaram, R. Ahmed. 1994. Cytotoxic T-cell memory without antigen. Nature 369: 648

Cousens, L. P., J. S. Orange, C. A. Biron. 1995. Endogenous IL-2 contributes to T cell expansion and IFN-γ production during lymphocytic choriomeningitis virus infection. J. Immunol. 155: 5690

Murata, K., S. A. Garcia, M. Tsuji, M. Rodrigues, D. Rodrigues, J. R. Rodriguez, R. S. Nussenzweig, P. Palese, M. Esteban, F. Zavala. 1996. Characterization of in vivo primary and secondary CD8+ T cell responses induced by recombinant influenza and vaccinia viruses. Cell. Immunol. 173: 96

Slifka, M. K., J. K. Whitmire, R. Ahmed. 1997. Bone marrow contains virus-specific cytotoxic T lymphocytes. Blood 90: 2103

Byrne, J. A., M. B. Oldstone. 1984. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J. Virol. 51: 682

Lehmann, G. F., D. Moskophidis, J. Lohler. 1988. Recovery from acute virus infection: role of cytotoxic T lymphocytes in the elimination of lymphocytic choriomeningitis virus from spleens of mice. Ann. NY Acad. Sci. 532: 238

Moskophidis, D., S. P. Cobbold, H. Waldmann, G. F. Lehmann. 1987. Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningitis virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response. J. Virol. 61: 1867

Ahmed, R., L. D. Butler, L. Bhatti. 1988. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J. Virol. 62: 2102

Whitmire, J. K., M. S. Asano, K. Murali-Krishna, M. Suresh, R. Ahmed. 1998. Long-term CD4 Th1 and Th2 memory following acute lymphocytic choriomeningitis virus infection. J. Virol. 72: 8281

Shahinian, A., K. Pfeffer, K. P. Lee, T. M. Kundig, K. Kishihara, A. Wakeham, K. Kawai, P. S. Ohashi, C. B. Thompson, T. W. Mak. 1993. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261: 609

Sigal, L. J., H. Reiser, K. L. Rock. 1998. The role of B7-1 and B7-2 costimulation for the generation of CTL responses in vivo. J. Immunol. 161: 2740

Wu, Y., Y. Liu. 1994. Viral induction of costimulatory activity on antigen-presenting cells bypasses the need for CD4+ T-cell help in CD8+ T-cell responses. Curr. Biol. 4: 499

Kwon, B. S., S. M. Weissman. 1989. cDNA sequences of two inducible T-cell genes. Proc. Natl. Acad. Sci. USA 86: 1963

Pollok, K. E., Y.-J. Kim, Z. Zhou, J. Hurtado, K. K. Kim, R. T. Pickard, B. S. Kwon. 1993. Inducible T cell antigen 4-1BB. J. Immunol. 150: 771

Alderson, M. R., C. A. Smith, T. W. Tough, T. Davis-Smith, R. J. Armitage, B. Falk, E. Roux, E. Baker, G. R. Sutherland, W. S. Din, R. G. Goodwin. 1994. Molecular and biological characterization of human 4-1BB and its ligand. Eur. J. Immunol. 24: 2219

Goodwin, R. G., W. S. Din, T. Davis-Smith, D. M. Anderson, S. D. Gimpel, T. Sato, A. C. Maliszewski, R. C. I. Brannan, N. G. Copeland, N. A. Jenkins, et al 1993. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur. J. Immunol. 23: 2631

Pollok, K. E., Y.-J. Kim, J. Hurtado, Z. Zhou, K. K. Kim, B. S. Kwon. 1994. 4-1BB T-cell antigen binds to mature B cells and macrophages, and costimulates anti-μ-primed splenic B cells. Eur. J. Immunol. 24: 367

DeBenedette, M. A., A. Shahinian, T. W. Mak, T. H. Watts. 1997. Costimulation of CD28− T lymphocytes by 4-1BB ligand. J. Immunol. 158: 551

DeBenedette, M. A., N. R. Chu, K. E. Pollok, J. Hurtado, W. F. Wade, B. S. Kwon, T. H. Watts. 1995. Role of 4-1BB ligand in costimulation of T lymphocyte growth and its up-regulation on M12 B lymphomas by cAMP. J. Exp. Med. 181: 985

Hurtado, J. C., S. H. Kim, K. E. Pollok, Z. H. Lee, B. S. Kwon. 1995. Potential role of 4-1BB in T cell activation: comparison with the costimulatory molecule CD28. J. Immunol. 155: 3360

Saoulli, K., S. Y. Lee, J. L. Cannons, W. C. Yeh, A. Santana, M. D. Goldstein, N. Bangia, M. A. DeBenedette, T. W. Mak, Y. Choi, T. H. Watts. 1998. CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J. Exp. Med. 187: 1849

Shuford, W. W., K. Klussman, D. D. Tritchler, D. T. Loo, J. Chalupny, A. W. Siadak, T. J. Brown, J. Emswiler, H. Raecho, C. P. Larsen, et al 1997. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186: 47

Melero, I., W. W. Shuford, S. A. Newby, A. Aruffo, J. A. Ledbetter, K. E. Hellstrom, R. S. Mittler, L. Chen. 1997. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3: 682

Renshaw, B. R., W. R. Fanslow, R. J. Armitage, K. A. Campbell, D. Liggitt, B. Wright, B. L. Davison, C. R. Maliszewski. 1994. Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180: 1889

Ahmed, R., A. Salmi, L. D. Butler, J. M. Chiller, M. B. Oldstone. 1984. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice: role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160: 521

Murali, K. K., J. D. Altman, M. Suresh, D. J. Sourdive, A. J. Zajac, J. D. Miller, J. Slansky, R. Ahmed. 1998. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8: 177

Slifka, M. K., M. Matloubian, R. Ahmed. 1995. Bone marrow is a major site of long-term antibody production after acute viral infection. J. Virol. 69: 1895

Linsley, P. S., P. M. Wallace, J. Johnson, M. G. Gibson, J. L. Greene, J. A. Ledbetter, C. Singh, M. A. Tepper. 1992. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257: 792

Larsen, C. P., E. T. Elwood, D. Z. Alexander, S. C. Ritchie, R. Hendrix, B. C. Tucker, H. R. Cho, A. Aruffo, D. Hollenbaugh, P. S. Linsley, et al 1996. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381: 434

Chen, L., P. S. Linsley, K. E. Hellstrom. 1993. Costimulation of T cells for tumor immunity. Immunol. Today 14: 483

Yang, G., M. T. Mizuno, K. E. Hellstrom, L. Chen. 1997. B7-negative versus B7-positive P815 tumor: differential requirements for priming of an antitumor immune response in lymph nodes. J. Immunol. 158: 851

Martin-Fontecha, A., F. Cavallo, M. Bellone, S. Heltai, G. Iezzi, P. Tornaghi, N. Nabavi, G. Forni, P. Dellabona, G. Casorati. 1996. Heterogeneous effects of B7-1 and B7-2 in the induction of both protective and therapeutic anti-tumor immunity against different mouse tumors. Eur. J. Immunol. 26: 1851

Melero, I., N. Bach, K. E. Hellstrom, A. Aruffo, R. S. Mittler, L. Chen. 1998. Amplification of tumor immunity by gene transfer of the costimulatory 4-1BB ligand: synergy with the CD28 costimulatory pathway. Eur. J. Immunol. 28: 1116

Whitmire, J. K., M. K. Slifka, I. S. Grewal, R. A. Flavell, R. Ahmed. 1996. CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection. J. Virol. 70: 8375

Whitmire, J. K., R. A. Flavell, C. P. Larsen, T. C. Pearson, R. Ahmed. 1999. Differential requirement of CD40-CD40 ligand costimulation for antiviral CD4 and CD8 T cell responses. J. Immunol. 163: 3194

Kim, Y. J., K. E. Pollok, Z. Zhou, A. Shaw, J. B. Bohlen, M. Fraser, B. S. Kwon. 1993. Novel T cell antigen 4-1BB associates with the protein tyrosine kinase p56lck1. J. Immunol. 151: 1255

Jang, I. K., Z. H. Lee, Y. J. Kim, S. H. Kim, B. S. Kwon. 1998. Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-κB. Biochem. Biophys. Res. Commun. 242: 613

Arch, R. H., C. B. Thompson. 1998. 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor κB. Mol. Cell. Biol. 18: 558

Viola, A., A. Lanzavecchia. 1996. T cell activation determined by T cell receptor number and tunable thresholds. Science 273: 104

Lenschow, D. J., T. L. Walunas, J. A. Bluestone. 1996. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14: 233

Ridge, J. P., F. Di Rosa, P. Matzinger. 1998. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393: 474

Bennett, S. R., F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. Miller, W. R. Heath. 1998. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393: 478

Schoenberger, S. P., R. E. Toes, E. I. van der Voort, R. Offringa, C. J. Melief. 1998. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393: 480

Guinn, B. A., M. A. DeBenedette, T. H. Watts, N. L. Berinstein. 1999. 4-1BBL cooperates with B7-1 and B7-2 in converting a B cell lymphoma cell line into a long-lasting antitumor vaccine. J. Immunol. 162: 5003

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Journal of Immunology

Tập 163 Số 9

4859-4868

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