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Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers
Includes bibliographical references.
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| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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Department of Paediatrics and Child Health
2014
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| _version_ | 1867613299452936192 |
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| access_status_str | Open Access |
| author | Dintwe, One Bridget |
| author2 | Scriba, Thomas J |
| author_browse | Dintwe, One Bridget Scriba, Thomas J |
| author_facet | Scriba, Thomas J Dintwe, One Bridget |
| author_sort | Dintwe, One Bridget |
| collection | Thesis |
| description | Includes bibliographical references. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/8713 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:33:55.830Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2014 |
| publishDateRange | 2014 |
| publishDateSort | 2014 |
| publisher | Department of Paediatrics and Child Health |
| publisherStr | Department of Paediatrics and Child Health |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/8713 Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers Dintwe, One Bridget Scriba, Thomas J Nemes, Elisa Includes bibliographical references. Tuberculosis (TB) remains a global health burden, with an estimated 1.3 million people dying from the disease in 2012. Protective immunity against TB is thought to depend on specific T cells. However, exactly which T cell characteristics are required for immunological protection is unknown. To gain a better understanding of M. tuberculosis (M.tb)-specific memory T cell immunity, we studied longevity and function of M.tb-specific memory T cells. We reasoned that such knowledge would facilitate rational vaccine design of a TB vaccine. We designed and developed a set of new HLA class II tetramers to perform in-depth studies of M.tb-specific CD4 T cell responses. We studied persons vaccinated with a novel TB vaccine, MVA85A, as well as persons naturally infected with M.tb. Antigen-specific CD4 T cells were detected with HLA class II tetramers and functional and phenotypic attributes of these T lymphocytes characterised by standard flow cytometric techniques. Comprehensive transcriptional analyses of M.tb-specific CD4 T cells, which were also sorted by FACS, were performed by microfluidic quantitative real-time PCR. Early after intradermal vaccination with MVA85A a large proportion of Ag85Aspecific CD4 T cells were highly activated, expressed skin homing markers and displayed an effector T cell phenotype. This effector response waned rapidly and gave way to antigen-specific central memory CD4 T cells with high proliferative potential, which we proposed may be desirable for protection. However, recent results from the first efficacy trial of MVA85A in infants suggested that these cells are not sufficient to enhance protection beyond that induced by BCG vaccination at birth. Further, we characterised surface marker expression and transcriptional signatures of a newly detected and described population of M.tb-specific CD4 T cells, that displayed a CD45RA+CCR7+CD27+ naïve-like T cell phenotype. We hypothesised that these unique M.tb-specific naïve-like CD4 T cells had a transcriptional profile distinct from truly naïve, central memory and effector bulk CD4 T cells, as well as other M.tb-specific memory CD4 T cell subsets. Gene expression of CFP10-specific naïve-like CD4 T cells reflected an mRNA profile that was very distinct from truly naïve bulk CD4 T cells. Rather, naïvelike CD4 T cells clustered with bulk effector CD4 T cells in unsupervised analysis methods such as hierarchical clustering and principle component analyses. Further analyses revealed that naïve-like CFP10-specific CD4 cells expressed mRNAs coding for effector cytokines, cytotoxic molecules and chemokine receptors consistent with effector memory T cells. However, the overall transcriptional profile was more similar to CFP10-specific central memory CD4 T cells than that of the effector CD4 T cells. We concluded that M.tb-specific naïve-like CD4 T cells may possess an ability to traffic to sites of infection or inflammation, where they may contribute to effector function. These hypotheses need confirmation on a protein level. The HLA class II tetramers developed in this thesis are valuabe tools for assessing direct ex vivo M.tb-specific CD4 T cell responses without activation and cell perturbation. Our findings contribute to a more comprehensive understanding of T cell immunity induced by vaccines and/or natural M.tb infection. 2014-10-21T13:53:54Z 2014-10-21T13:53:54Z 2014 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/8713 eng application/pdf Department of Paediatrics and Child Health Faculty of Health Sciences University of Cape Town |
| spellingShingle | Dintwe, One Bridget Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| thesis_degree_str | Doctoral |
| title | Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| title_full | Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| title_fullStr | Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| title_full_unstemmed | Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| title_short | Characterisation of Mycobacterium tuberculosis specific T cell immunity with HLA class II tetramers |
| title_sort | characterisation of mycobacterium tuberculosis specific t cell immunity with hla class ii tetramers |
| url | http://hdl.handle.net/11427/8713 |
| work_keys_str_mv | AT dintweonebridget characterisationofmycobacteriumtuberculosisspecifictcellimmunitywithhlaclassiitetramers |