This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhou, S.
Right arrow Articles by Moskophidis, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhou, S.
Right arrow Articles by Moskophidis, D.

 Previous Article  |  Next Article 

Journal of Virology, January 2002, p. 829-840, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.829-840.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Critical Role for Perforin-, Fas/FasL-, and TNFR1-Mediated Cytotoxic Pathways in Down-Regulation of Antigen-Specific T Cells during Persistent Viral Infection

Shenghua Zhou, Rong Ou, Lei Huang, and Demetrius Moskophidis*

Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912

Received 24 July 2001/ Accepted 11 October 2001

Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation of virus-specific T lymphocytes. High viral burden in the onset of infection drives responding cells into functional unresponsiveness (anergy) that can be followed by their physical elimination. In this report, we studied down-regulation of the virus-specific CD8+-T-cell response during persistent infection of adult mice with LCMV, with emphasis on the role of perforin-, Fas/FasL-, or tumor necrosis factor receptor 1 (TNFR1)-mediated cytolysis in regulating T-cell homeostasis. The results reveal that the absence of perforin, Fas-ligand, or TNFR1 has no significant effect on the kinetics of proliferation and functional inactivation of virus-specific CD8+ T cells in the onset of chronic LCMV infection. However, these molecules play a critical role in the homeostatic regulation of T cells, influencing the longevity of the virus-specific CD8+-T-cell population once it has become anergic. Thus, CD8+ T cells specific to the dominant LCMV NP396–404 epitope persist in an anergic state for at least 70 days in perforin-, FasL-, or TNFR1-deficient mice, but they were eliminated by day 30 in C57BL/6 controls. These effects were additive as shown by a deficit of apoptotic death of NP396–404 peptide-specific CD8+ T cells in mice lacking both perforin and TNFR1. This suggests a role for perforin-, FasL-, and TNFR1-mediated pathways in down-regulation of the antiviral T cell response during persistent viral infection by determining the fate of antigen-specific T cells. Moreover, virus-specific anergic CD8+ T cells in persistently infected C57BL/6 mice contain higher levels of Bcl-2 and Bcl-XL than functionally intact T cells generated during acute LCMV infection. In the case of proapoptotic factors, Bax expression did not differ between T-cell populations and Bad was below the limit of detection in all samples. As expression of the Bcl-2 family members controls susceptibility to apoptosis, this finding may provide a molecular basis for the survival of anergic cells under conditions of prolonged antigen stimulation.

* Corresponding author. Mailing address: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th St. CB-2803, Augusta, GA 30912-3175. Phone: (706) 721-8738. Fax: (706) 721-8732. E-mail: moskophidis{at}immagene.mcg.edu.

Journal of Virology, January 2002, p. 829-840, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.829-840.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bucks, C. M., Norton, J. A., Boesteanu, A. C., Mueller, Y. M., Katsikis, P. D. (2009). Chronic Antigen Stimulation Alone Is Sufficient to Drive CD8+ T Cell Exhaustion. J. Immunol. 182: 6697-6708 [Abstract] [Full Text]  
  • Ou, R., Zhang, M., Huang, L., Moskophidis, D. (2008). Control of Virus-Specific CD8+ T-Cell Exhaustion and Immune-Mediated Pathology by E3 Ubiquitin Ligase Cbl-b during Chronic Viral Infection. J. Virol. 82: 3353-3368 [Abstract] [Full Text]  
  • Orilieri, E., Cappellano, G., Clementi, R., Cometa, A., Ferretti, M., Cerutti, E., Cadario, F., Martinetti, M., Larizza, D., Calcaterra, V., D'Annunzio, G., Lorini, R., Cerutti, F., Bruno, G., Chiocchetti, A., Dianzani, U. (2008). Variations of the Perforin Gene in Patients With Type 1 Diabetes. Diabetes 57: 1078-1083 [Abstract] [Full Text]  
  • Belnoue, E., Fontannaz-Bozzotti, P., Grillet, S., Lambert, P.-H., Siegrist, C.-A. (2007). Protracted Course of Lymphocytic Choriomeningitis Virus WE Infection in Early Life: Induction but Limited Expansion of CD8+ Effector T Cells and Absence of Memory CD8+ T Cells. J. Virol. 81: 7338-7350 [Abstract] [Full Text]  
  • Li, X., McKinstry, K. K., Swain, S. L., Dalton, D. K. (2007). IFN-{gamma} Acts Directly on Activated CD4+ T Cells during Mycobacterial Infection to Promote Apoptosis by Inducing Components of the Intracellular Apoptosis Machinery and by Inducing Extracellular Proapoptotic Signals. J. Immunol. 179: 939-949 [Abstract] [Full Text]  
  • Guillermo, L. V. C., Silva, E. M., Ribeiro-Gomes, F. L., De Meis, J., Pereira, W. F., Yagita, H., DosReis, G. A., Lopes, M. F. (2007). The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection. J. Leukoc. Biol. 81: 942-951 [Abstract] [Full Text]  
  • Van Dyken, S. J., Green, R. S., Marth, J. D. (2007). Structural and Mechanistic Features of Protein O Glycosylation Linked to CD8+ T-Cell Apoptosis. Mol. Cell. Biol. 27: 1096-1111 [Abstract] [Full Text]  
  • Bartholdy, C., Kauffmann, S. O., Christensen, J. P., Thomsen, A. R. (2007). Agonistic Anti-CD40 Antibody Profoundly Suppresses the Immune Response to Infection with Lymphocytic Choriomeningitis Virus. J. Immunol. 178: 1662-1670 [Abstract] [Full Text]  
  • Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U. (2006). Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function. Blood 108: 3079-3084 [Abstract] [Full Text]  
  • Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D. A., Gostick, E., Adams, W. C., Precopio, M. L., Schacker, T., Roederer, M., Douek, D. C., Koup, R. A. (2006). PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. JEM 203: 2281-2292 [Abstract] [Full Text]  
  • Grayson, J. M., Weant, A. E., Holbrook, B. C., Hildeman, D. (2006). Role of Bim in Regulating CD8+ T-Cell Responses during Chronic Viral Infection.. J. Virol. 80: 8627-8638 [Abstract] [Full Text]  
  • Saito, K., Yajima, T., Kumabe, S., Doi, T., Yamada, H., Sad, S., Shen, H., Yoshikai, Y. (2006). Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guerin Infection in IL-15-Deficient Mice. J. Immunol. 176: 2496-2504 [Abstract] [Full Text]  
  • Storm, P., Bartholdy, C., Sorensen, M. R., Christensen, J. P., Thomsen, A. R. (2006). Perforin-Deficient CD8+ T Cells Mediate Fatal Lymphocytic Choriomeningitis despite Impaired Cytokine Production. J. Virol. 80: 1222-1230 [Abstract] [Full Text]  
  • Wang, X. Z., Brehm, M. A., Welsh, R. M. (2004). Preapoptotic Phenotype of Viral Epitope-Specific CD8 T Cells Precludes Memory Development and Is an Intrinsic Property of the Epitope. J. Immunol. 173: 5138-5147 [Abstract] [Full Text]  
  • Phillips, T., Opferman, J. T., Shah, R., Liu, N., Froelich, C. J., Ashton-Rickardt, P. G. (2004). A Role for the Granzyme B Inhibitor Serine Protease Inhibitor 6 in CD8+ Memory Cell Homeostasis. J. Immunol. 173: 3801-3809 [Abstract] [Full Text]  
  • Wherry, E. J., Ahmed, R. (2004). Memory CD8 T-Cell Differentiation during Viral Infection. J. Virol. 78: 5535-5545 [Full Text]  
  • Homann, D., McGavern, D. B., Oldstone, M. B. A. (2004). Visualizing the Viral Burden: Phenotypic and Functional Alterations of T Cells and APCs during Persistent Infection. J. Immunol. 172: 6239-6250 [Abstract] [Full Text]  
  • Suresh, M., Gao, X., Fischer, C., Miller, N. E., Tewari, K. (2004). Dissection of Antiviral and Immune Regulatory Functions of Tumor Necrosis Factor Receptors in a Chronic Lymphocytic Choriomeningitis Virus Infection. J. Virol. 78: 3906-3918 [Abstract] [Full Text]  
  • Zhou, S., Ou, R., Huang, L., Price, G. E., Moskophidis, D. (2004). Differential Tissue-Specific Regulation of Antiviral CD8+ T-Cell Immune Responses during Chronic Viral Infection. J. Virol. 78: 3578-3600 [Abstract] [Full Text]  
  • Petrovas, C., Mueller, Y. M., Dimitriou, I. D., Bojczuk, P. M., Mounzer, K. C., Witek, J., Altman, J. D., Katsikis, P. D. (2004). HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL. J. Immunol. 172: 4444-4453 [Abstract] [Full Text]  
  • Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R., Ahmed, R. (2003). Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment. J. Virol. 77: 4911-4927 [Abstract] [Full Text]  
  • Fuller, M. J., Zajac, A. J. (2003). Ablation of CD8 and CD4 T Cell Responses by High Viral Loads. J. Immunol. 170: 477-486 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»