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Early Virus-Associated Bystander Events Affect the Fitness of the CD8 T Cell Response to Persistent Virus Infection¹

Nicolas P. Andrews^*, Christopher D. Pack^*, Vaiva Vezys^*, Glen N. Barber and Aron E. Lukacher^2,*

^* Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322; and Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136

Chronic Ag exposure during persistent viral infection erodes virus-specific CD8 T cell numbers and effector function, with a concomitant loss of pathogen control. Less clear are the respective contributions of Ag-specific and Ag-nonspecific (bystander) events on the quantity, quality, and maintenance of antiviral CD8 T cells responding to persistent virus infection. In this study, we show that low-dose inoculation with mouse polyomavirus (PyV) elicits a delayed, but numerically equivalent, antiviral CD8 T cell response compared with high-dose inoculation. Low-dose infection generated virus-specific CD8 T cells endowed with multicytokine functionality and a superior per cell capacity to produce IFN-. PyV-specific CD8 T cells primed by low-dose inoculation also expressed higher levels of IL-7R and bcl-2 and possessed enhanced Ag-independent survival. Importantly, the quantity and quality of the antiviral CD8 T cell response elicited by dendritic cell-mediated immunization were mitigated by infection with a mutant PyV lacking the dominant CD8 T cell viral epitope. These findings suggest that the fitness of the CD8 T cell response to persistent virus infection is programmed in large part by early virus-associated Ag-nonspecific factors, and imply that limiting bystander inflammation at the time of inoculation, independent of Ag load, may optimize adaptive immunity to persistent viral infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1CA71971 and RO1CA100644 (to A.E.L.), RO1CA095924 (to G.N.B.), and F32CA106090 (to V.V.).

² Address correspondence and reprint requests to Dr. Aron E. Lukacher, Department of Pathology, Woodruff Memorial Research Building, Room 7307, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322. E-mail address: alukach{at}emory.edu

³ Abbreviations used in this paper: DC, dendritic cell; FasL, Fas ligand; LT, large T Ag; MFI, mean fluorescence intensity; nPyV, LT359–368 epitope-null polyomavirus; p.i., postinfection; PyV, polyomavirus; VSV, vesicular stomatitis virus.

This article has been cited by other articles:

				N. P. Andrews, C. D. Pack, and A. E. Lukacher Generation of Antiviral Major Histocompatibility Complex Class I-Restricted T Cells in the Absence of CD8 Coreceptors J. Virol., May 15, 2008; 82(10): 4697 - 4705. [Abstract] [Full Text] [PDF]

				C. C. Kemball, E. Szomolanyi-Tsuda, and A. E. Lukacher Allogeneic Differences in the Dependence on CD4+ T-Cell Help for Virus-Specific CD8+ T-Cell Differentiation J. Virol., December 15, 2007; 81(24): 13743 - 13753. [Abstract] [Full Text] [PDF]