Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

doi:10.1084/jem.188.12.2205

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J. Exp. Med., Volume 188, Number 12, December 21, 1998 2205-2213

Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

By Allan J. Zajac, Joseph N. Blattman, Kaja Murali-Krishna, David J.D. Sourdive, M. Suresh, John D. Altman, and Rafi Ahmed

From the Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322

We examined the regulation of virus-specific CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV)infection of mice. Our study shows that within the same persistentlyinfected host, different mechanisms can operate to silence antiviralT cell responses; CD8 T cells specific to one dominant viral epitopewere deleted, whereas CD8 T cells responding to another dominantepitope persisted indefinitely. These virus-specific CD8 T cellsexpressed activation markers (CD69^hi, CD44^hi, CD62L^lo) and proliferated in vivo but were unable to elaborate any antiviraleffector functions. This unresponsive phenotype was more pronouncedunder conditions of CD4 T cell deficiency, highlighting the importanceof CD8- CD4 T cell collaboration in controlling persistent infections.Importantly, in the presence of CD4 T cell help, adequate CD8effector activity was maintained and the chronic viral infectioneventually resolved. The persistence of activated virus-specificCD8 T cells without effector function reveals a novel mechanismfor silencing antiviral immune responses and also offers new possibilitiesfor enhancing CD8 T cell immunity in chronically infected hosts.

Key words: cytotoxic T cells; unresponsiveness; chronic infections; CD4 T cells; major histocompatibility complex tetramers

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Byers, A. M., Andrews, N. P., Lukacher, A. E. (2006). CD94/NKG2A Expression Is Associated with Proliferative Potential of CD8 T Cells during Persistent Polyoma Virus Infection. J. Immunol. 176: 6121-6129 [Abstract] [Full Text]
Boettler, T., Panther, E., Bengsch, B., Nazarova, N., Spangenberg, H. C., Blum, H. E., Thimme, R. (2006). Expression of the Interleukin-7 Receptor Alpha Chain (CD127) on Virus-Specific CD8+ T Cells Identifies Functionally and Phenotypically Defined Memory T Cells during Acute Resolving Hepatitis B Virus Infection.. J. Virol. 80: 3532-3540 [Abstract] [Full Text]
Okazaki, T., Pendleton, C. D., Sarobe, P., Thomas, E. K., Iyengar, S., Harro, C., Schwartz, D., Berzofsky, J. A. (2006). Epitope Enhancement of a CD4 HIV Epitope toward the Development of the Next Generation HIV Vaccine. J. Immunol. 176: 3753-3759 [Abstract] [Full Text]
Ramer, A. E., Vanloubbeeck, Y. F., Jones, D. E. (2006). Antigen-Responsive CD4+ T Cells from C3H Mice Chronically Infected with Leishmania amazonensis Are Impaired in the Transition to an Effector Phenotype. Infect. Immun. 74: 1547-1554 [Abstract] [Full Text]
Cayabyab, M. J., Hovav, A.-H., Hsu, T., Krivulka, G. R., Lifton, M. A., Gorgone, D. A., Fennelly, G. J., Haynes, B. F., Jacobs, W. R. Jr., Letvin, N. L. (2006). Generation of CD8+ T-Cell Responses by a Recombinant Nonpathogenic Mycobacterium smegmatis Vaccine Vector Expressing Human Immunodeficiency Virus Type 1 Env. J. Virol. 80: 1645-1652 [Abstract] [Full Text]
Kemball, C. C., Lee, E. D. H., Szomolanyi-Tsuda, E., Pearson, T. C., Larsen, C. P., Lukacher, A. E. (2006). Costimulation Requirements for Antiviral CD8+ T Cells Differ for Acute and Persistent Phases of Polyoma Virus Infection. J. Immunol. 176: 1814-1824 [Abstract] [Full Text]
Yang, T.-C., Millar, J., Groves, T., Grinshtein, N., Parsons, R., Takenaka, S., Wan, Y., Bramson, J. L. (2006). The CD8+ T Cell Population Elicited by Recombinant Adenovirus Displays a Novel Partially Exhausted Phenotype Associated with Prolonged Antigen Presentation That Nonetheless Provides Long-Term Immunity. J. Immunol. 176: 200-210 [Abstract] [Full Text]
Piriou, E., van Dort, K., Nanlohy, N. M., van Oers, M. H. J., Miedema, F., van Baarle, D. (2005). Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma. Blood 106: 3166-3174 [Abstract] [Full Text]
Bachmann, M. F., Wolint, P., Schwarz, K., Jager, P., Oxenius, A. (2005). Functional Properties and Lineage Relationship of CD8+ T Cell Subsets Identified by Expression of IL-7 Receptor {alpha} and CD62L. J. Immunol. 175: 4686-4696 [Abstract] [Full Text]