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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.



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Copyright © 2002 by the American Society for Microbiology. All rights reserved.