Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection
<p>During the course of infection with chronic pathogens such as Hepatitis C virus (HCV), Hepatitis B virus (HBV) and HIV, virus-specific CD8<sup>&plus;</sup> T cells differentiate into heterogeneous dysfunctional subpopulations. Advances in multi-parameter flow cytometry h...
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| Andere auteurs: | |
| Formaat: | Thesis |
| Taal: | English |
| Gepubliceerd in: |
2014
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| _version_ | 1826304612547690496 |
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| author | Gupta, P |
| author2 | Klenerman, P |
| author_facet | Klenerman, P Gupta, P |
| author_sort | Gupta, P |
| collection | OXFORD |
| description | <p>During the course of infection with chronic pathogens such as Hepatitis C virus (HCV), Hepatitis B virus (HBV) and HIV, virus-specific CD8<sup>&plus;</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>&plus;</sup> T cells during exhaustion is an area of great interest as many inhibitory receptors are also expressed on functional CD8<sup>&plus;</sup> T cells. Discovering novel and specific markers of T cell exhaustion is fundamental in developing strategies to restore CD8<sup>&plus;</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>&plus;</sup> T cell exhaustion in chronic viral infection. I show that CD39 is highly expressed in HCV and HIV-specific CD8<sup>&plus;</sup> T cells and that CD39<sup>&plus;</sup> CD8<sup>&plus;</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>&plus;</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>&plus;</sup> fraction. Thus, CD39 is a novel and specific marker of severe CD8<sup>&plus;</sup> T cell exhaustion in human and animal models of chronic viral infection.</p> |
| first_indexed | 2024-03-07T06:20:28Z |
| format | Thesis |
| id | oxford-uuid:f28b67d7-287d-4594-a2d1-161f35e9c5a2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:20:28Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:f28b67d7-287d-4594-a2d1-161f35e9c5a22022-03-27T12:04:40ZUse of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infectionThesishttp://purl.org/coar/resource_type/c_db06uuid:f28b67d7-287d-4594-a2d1-161f35e9c5a2GastroenterologyMedical sciencesGenetics (medical sciences)Infectious diseasesImmunologyEnglishOxford University Research Archive - Valet2014Gupta, PKlenerman, PHaining, W<p>During the course of infection with chronic pathogens such as Hepatitis C virus (HCV), Hepatitis B virus (HBV) and HIV, virus-specific CD8<sup>&plus;</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>&plus;</sup> T cells during exhaustion is an area of great interest as many inhibitory receptors are also expressed on functional CD8<sup>&plus;</sup> T cells. Discovering novel and specific markers of T cell exhaustion is fundamental in developing strategies to restore CD8<sup>&plus;</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>&plus;</sup> T cell exhaustion in chronic viral infection. I show that CD39 is highly expressed in HCV and HIV-specific CD8<sup>&plus;</sup> T cells and that CD39<sup>&plus;</sup> CD8<sup>&plus;</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>&plus;</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>&plus;</sup> fraction. Thus, CD39 is a novel and specific marker of severe CD8<sup>&plus;</sup> T cell exhaustion in human and animal models of chronic viral infection.</p> |
| spellingShingle | Gastroenterology Medical sciences Genetics (medical sciences) Infectious diseases Immunology Gupta, P Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title | Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title_full | Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title_fullStr | Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title_full_unstemmed | Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title_short | Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection |
| title_sort | use of genome wide expression profiles in analysis of t cell dysfunction in hepatitis c virus infection |
| topic | Gastroenterology Medical sciences Genetics (medical sciences) Infectious diseases Immunology |
| work_keys_str_mv | AT guptap useofgenomewideexpressionprofilesinanalysisoftcelldysfunctioninhepatitiscvirusinfection |