Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31

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dc.contributor.advisorScriba, Thomas Jen_ZA
dc.contributor.advisorPenn-Nicholson, Adamen_ZA
dc.contributor.authorMusvosvi, Munyaradzi Nyashaen_ZA
dc.date.accessioned2016-02-03T14:29:28Z
dc.date.available2016-02-03T14:29:28Z
dc.date.issued2015en_ZA
dc.descriptionIncludes bibliographical referencesen_ZA
dc.description.abstractIn this study we sought to more comprehensively analyse antigen-specific CD4 T cell responses induced by vaccination and to examine the effects of latent M. tb infection on these responses. We had two broad objectives: Firstly, to determine the effects of latent M. tb infection on epitope recognition by mycobacteria-specific CD4 T cells and to design HLA class II tetramers for detection of these cells. Secondly, to characterise antigen-specific CD4 T cells following vaccination with the novel vaccine candidate, H1:IC31, by measuring transcriptomic, phenotypic and functional attributes, and to determine the effects of latent infection on these responses. Firstly, we found that acquisition of M.tb infection did not alter the breadth and/or pattern of Ag85A/ B CD4 T cell epitopes recognised. We determined the HLA allele restriction of identified epitopes, and designed HLA class II tetramers for detection of Ag85-specific CD4 T cells. These results suggest that latent infection does not alter CD4 T cell epitope breadth within Ag85A/ B elicited by BCG vaccination and/or exposure to environmental mycobacteria. The second finding of this work is that underlying infection drives a more effector-like H1-specific CD4 T response after vaccination. Following vaccination M. tb-infected adolescents had higher frequencies of H1-specific CD4 T cells compared with uninfected adolescents. Additionally, H1-specific CD4 T cells from infected adolescents predominantly displayed a CCR7 - CD45RA - effector memory phenotype, had higher proportions of IFN-γ + TNF-α + IL-2 + cells, and expressed higher levels mRNA transcripts encoding effector molecules such as granzyme K and perforin, compared with uninfected adolescents. By contrast, H1-specific CD4 T cells in uninfected adolescents displayed a less differentiated memory phenotype, and had increased expression of central memory genes, compared to cells from infected adolescents. Thirdly, we found that Ag85B and ESAT-6-specific CD4 T cells exhibited markedly distinct transcriptomic profiles, memory phenotypes and cytokine expression patterns in M.tb infected adolescents. The data suggested that ESAT-6-specific cells preferentially drove the effector-like H1-specific response in M.tb infected adolescents. We conclude that while underlying M.tb infection does not affect the epitopes recognized by mycobacteria-specific CD4 T cells, but may promote and maintain effector memory antigen-specific CD4 T cells endowed with immediate effector function and tissue homing.en_ZA
dc.identifier.apacitationMusvosvi, M. N. (2015). <i>Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Department of Paediatrics and Child Health. Retrieved from http://hdl.handle.net/11427/16724en_ZA
dc.identifier.chicagocitationMusvosvi, Munyaradzi Nyasha. <i>"Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Department of Paediatrics and Child Health, 2015. http://hdl.handle.net/11427/16724en_ZA
dc.identifier.citationMusvosvi, M. 2015. Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Musvosvi, Munyaradzi Nyasha AB - In this study we sought to more comprehensively analyse antigen-specific CD4 T cell responses induced by vaccination and to examine the effects of latent M. tb infection on these responses. We had two broad objectives: Firstly, to determine the effects of latent M. tb infection on epitope recognition by mycobacteria-specific CD4 T cells and to design HLA class II tetramers for detection of these cells. Secondly, to characterise antigen-specific CD4 T cells following vaccination with the novel vaccine candidate, H1:IC31, by measuring transcriptomic, phenotypic and functional attributes, and to determine the effects of latent infection on these responses. Firstly, we found that acquisition of M.tb infection did not alter the breadth and/or pattern of Ag85A/ B CD4 T cell epitopes recognised. We determined the HLA allele restriction of identified epitopes, and designed HLA class II tetramers for detection of Ag85-specific CD4 T cells. These results suggest that latent infection does not alter CD4 T cell epitope breadth within Ag85A/ B elicited by BCG vaccination and/or exposure to environmental mycobacteria. The second finding of this work is that underlying infection drives a more effector-like H1-specific CD4 T response after vaccination. Following vaccination M. tb-infected adolescents had higher frequencies of H1-specific CD4 T cells compared with uninfected adolescents. Additionally, H1-specific CD4 T cells from infected adolescents predominantly displayed a CCR7 - CD45RA - effector memory phenotype, had higher proportions of IFN-γ + TNF-α + IL-2 + cells, and expressed higher levels mRNA transcripts encoding effector molecules such as granzyme K and perforin, compared with uninfected adolescents. By contrast, H1-specific CD4 T cells in uninfected adolescents displayed a less differentiated memory phenotype, and had increased expression of central memory genes, compared to cells from infected adolescents. Thirdly, we found that Ag85B and ESAT-6-specific CD4 T cells exhibited markedly distinct transcriptomic profiles, memory phenotypes and cytokine expression patterns in M.tb infected adolescents. The data suggested that ESAT-6-specific cells preferentially drove the effector-like H1-specific response in M.tb infected adolescents. We conclude that while underlying M.tb infection does not affect the epitopes recognized by mycobacteria-specific CD4 T cells, but may promote and maintain effector memory antigen-specific CD4 T cells endowed with immediate effector function and tissue homing. DA - 2015 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31 TI - Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31 UR - http://hdl.handle.net/11427/16724 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16724
dc.identifier.vancouvercitationMusvosvi MN. Systems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Department of Paediatrics and Child Health, 2015 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/16724en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Paediatrics and Child Healthen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherPaediatrics and Child Healthen_ZA
dc.titleSystems analysis of the CD4 T cell response induced by the novel subunit tuberculosis vaccine, H1:IC31en_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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