During the course of infection with chronic pathogens such as Hepatitis C virus (HCV), Hepatitis B virus (HBV) and HIV, virus-specific CD8<sup>+</sup> T cells differentiate into heterogeneous dysfunctional subpopulations. Advances in multi-parameter flow cytometry have allowed these subpopulations to be further classified into classes of exhausted T cells, primarily by their expression of multiple inhibitory receptors. However, the exact phenotype of CD8<sup>+</sup> T cells during exhaustion is an area of great interest as many inhibitory receptors are also expressed on functional CD8<sup>+</sup> T cells. Discovering novel and specific markers of T cell exhaustion is fundamental in developing strategies to restore CD8<sup>+</sup> T cell function in chronic viral infections. Recently, genome wide expression profiles have identified broad molecular phenotypes in exhausted T cells that could not have been discovered by flow cytometry alone. I show how similar genomic approaches identify and further characterise the ectonucleotidase CD39 as a novel marker of CD8<sup>+</sup> T cell exhaustion in chronic viral infection. I show that CD39 is highly expressed in HCV and HIV-specific CD8<sup>+</sup> T cells and that CD39<sup>+</sup> CD8<sup>+</sup> T cells are enriched with gene signatures of exhaustion. CD39 is highly co-expressed with multiple inhibitory receptors including PD-1, enzymatically active on CD8<sup>+</sup> T cells in HCV infection and positively correlated with viral load in both HCV and HIV. I also demonstrate the discovery of a novel CD39<sup>High</sup> population of cells in the mouse model of chronic Lymphocytic Choriomenigitis Virus (LCMV) infection, which express the highest degrees of PD-1, LAG3 and 2B4 in the CD39<sup>+</sup> fraction. Thus, CD39 is a novel and specific marker of severe CD8<sup>+</sup> T cell exhaustion in human and animal models of chronic viral infection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:655052 |
| Date | January 2014 |
| Creators | Gupta, Prakash K. |
| Contributors | Klenerman, Paul; Haining, W. Nicholas |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:f28b67d7-287d-4594-a2d1-161f35e9c5a2 |
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