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Published online ahead of print on 25 March 2009 as doi:10.1099/vir.0.009837-0
Journal of General Virology 2009;90:1692.

A more recent version of this article appeared on July 1, 2009 J Gen Virol (2009), DOI 10.1099/vir.0.009837-0
© 2009 Society for General Microbiology
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Determinants of in vitro expansion of different human virus-specific FoxP3+ regulatory CD8+ T cells in chronic HCV infection

Eva Billerbeck1, Nobuhiro Nakamoto2, Bianca Seigel3, Hubert E. Blum4, Kyong-Mi Chang2 and Robert Thimme5,6

1 Department of Medicine II Universitiy of Freiburg, Germany;
2 University of Pennsylvania, Philadelphia, Pennsylvania, USA;
3 Department of Medicine II, University of Freiburg, Germany;
4 Department of Medicine II, Universtiy of Freiburg, Germany;
5 Department of Medicine II, University Hospital Freiburg

6 E-mail: thimme{at}med1.ukl.uni-freiburg.de

We previously showed that suppressive virus-specific FoxP3+ regulatory CD8+ T cells can be expanded from human PBMC after in vitro antigen-specific stimulation. Here we extend this finding by analyzing the mechanisms of virus-specific FoxP3+ regulatory CD8+ T cells generation during peptide-specific expansion in vitro. We show that hepatitis C virus (HCV)-, influenza virus (Flu)-, Epstein-Barr virus (EBV)- and cytomegalovirus (CMV)-specific FoxP3+ regulatory CD8+ T cells can be differentially expanded from the blood of chronically HCV infected patients upon in vitro peptide-specific stimulation. The different ability of virus-specific CD8+ T cell populations to express FoxP3 after continuous antigen stimulation in vitro thereby significantly correlates with the ex vivo differentiation status. Indeed, CD27+CD28+CD57- HCV-, Flu- and EBV-specific CD8+ T cells display a significantly higher ability to give rise to FoxP3+ regulatory CD8+ T cells compared to CD27-CD28-CD57+ CMV-specific CD8+ T cells. Similar TCR expression patterns of FoxP3+ versus FoxP3- CD8+ T cells of the same antigen-specificity indicate that both cell populations are most likely expanded from the same virus-specific CD8+ T cell precursor. In addition, no specific antigen presenting cell populations are required for the generation of FoxP3+ CD8+ T cells since CD8+ selected virus-specific FoxP3+CD8+ T cells can be expanded by peptide-presentation in the absence of antigen-presenting cells. Taken together, our results suggest that the ability to expand FoxP3+ regulatory CD8+ T cells from virus-specific CD8+ T cells differs between distinct virus-specific CD8+ T cell populations depending on the differentiation status.

Received 19 December 2008; accepted 19 March 2009.




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