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Journal of Virology, April 2003, p. 4911-4927, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4911-4927.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

E. John Wherry, Joseph N. Blattman,{dagger} Kaja Murali-Krishna,{ddagger} Robbert van der Most,§ and Rafi Ahmed*

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

Received 12 September 2002/ Accepted 4 December 2002

Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.

* Corresponding author. Mailing address: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, G211 Rollins Research Building, 1510 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-4700. Fax: (404) 727-3722. E-mail: ra{at}microbio.emory.edu.

{dagger} Present address: Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024.

{ddagger} Present address: Department of Immunology, H574 HSC, University of Washington, Seattle, WA 98195.

§ Present address: Department of Immunology, Faculty of Veterinary Medicine, 3584 CL Utrecht, The Netherlands.

Journal of Virology, April 2003, p. 4911-4927, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4911-4927.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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