Oncogenic DNA viruses establish persistent infection and continuous immunosurveillance by CD8+ T lymphocytes is often essential for eliminating infected and newly transformed cells. The effector activity of antiviral CD8+ T cells must be tightly balanced to control persistent infection without causing pathology resulting from excessive destruction of infected cells. Resistance to polyoma virus, a highly oncogenic persistent mouse pathogen, is mediated by antiviral CD8+ T cells. Mice susceptible to polyoma-induced tumors mount a substantial expansion of polyoma-specific CD8+ T cells during acute infection, but these T cells lack antigen-specific cytotoxicity. An inhibitory NK cell receptor, CD94/NKG2A, is expressed by polyoma-specific CD8+ T cells and is responsible for quenching their antigen-specific cytotoxicity. The proportion of anti-polyoma CD8+ T cells expressing CD94/NKG2A receptors increases in concert with clearance of infectious virus in polyoma tumor-resistant mice. Our overall hypothesis is that excessive TCR stimulation by cognate viral antigens and/or overproduction of specific cytokines early in acute infection in susceptible mice prematurely induces CD94/NKG2A expression on, and inhibits effector activity by, anti-polyoma CD8+ T cells; this leads to elevated numbers of persistently infected cells and an enhanced predisposition to viral oncogenesis. Studies proposed in this application seek (1) to define in vivo factors that regulate and maintain CD94/NKG2A expression by anti-polyoma CD8+ T cells, and (2) to investigate the potential role for this inhibitory receptor in regulating polyoma-specific memory' CD8+ T cell homeostasis in the setting of persistent viral infection. Polyoma-specific CD8+ T cells will be visualized physically using MHC class I tetramers and functionally by intracellular cytokine production, cytokine secretion, and cytotoxicity (both ex vivo and in vivo) assays. Defining in vivo mechanisms that induce and maintain expression of inhibitory NK cell receptors on antiviral CD8+ T cells may prove key to devising strategies to manipulate dysregulated antiviral immune responses and control persistent viral infections. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100644-04
Application #
7060901
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Howcroft, Thomas K
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$264,202
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Byers, Anthony M; Andrews, Nicolas P; Lukacher, Aron E (2006) CD94/NKG2A expression is associated with proliferative potential of CD8 T cells during persistent polyoma virus infection. J Immunol 176:6121-9

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