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dc.contributor.advisorLetvin, Norman
dc.contributor.authorSircar, Piya
dc.date.accessioned2013-02-26T17:21:07Z
dc.date.issued2013-02-26
dc.date.submitted2011
dc.identifier.citationSircar, Piya. 2011. Clonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responses. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:10035en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10345145
dc.description.abstractCD8+ T cells responses are critical in the immune defense against human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. A major challenge for vaccine development is that HIV/SIV can rapidly mutate to escape containment by the CD8+ T cell response. Therefore, optimal virus control by a vaccine will likely require clonally diverse CD8+ T cells capable of recognizing mutant viruses. Mucosal tissues play a fundamental role in early HIV/SIV pathogenesis by serving as the site for viral entry, CD4+ T cell depletion, and a reservoir for viral replication. Vaccine strategies that induce effective mucosal immunity will likely be critical for protection against HIV/SIV. We examined the SIV Gag p11C-specific CD8+ T cell responses in peripheral blood, gastrointestinal (GI) mucosal and lung mucosal tissues of rhesus monkeys expressing the MHC class I molecule Mamu-A*01. We first investigated the clonal composition of this cell population during the acute and chronic phases of SIVmac infection. We showed that there is a narrowing of the clonal repertoire from acute to chronic infection and the same clonal populations of virus-specific CD8+ T cells are present in the systemic and mucosal compartments of chronically SIV-infected animals. These data indicated that virus-specific CD8+ T cells establish broadly distributed immune responses. Next, we examined the clonal diversity of systemic and mucosal p11C-specific CD8+ T cells induced by prime-boost vaccination. We found that systemic prime-boost vaccination induced clonally diverse p11C-specific populations in mucosal tissues. There were high levels of clonal sharing between systemic and mucosal compartments soon after vaccination. However, later following vaccination there was decreased clonal sharing between the GI mucosa and the systemic circulation. We showed that this was due to limited trafficking of p11C-specific CD8+ T cells to the GI mucosa following vaccination. Overall, these studies indicate that following SIV infection and systemic vaccination the same p11C-specific clones are present in mucosal and systemic compartments. Moreover, the apparent immune compartmentalization is a consequence of differences in cell trafficking between systemic and mucosal CD8+ T cells. These observations have important implications for the design of HIV vaccines that generate effective mucosal immunity.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectCD8+ T cellsen_US
dc.subjectmucosal tissuesen_US
dc.subjectrhesus monkeysen_US
dc.subjectvaccinesen_US
dc.subjectimmunologyen_US
dc.subjectHIVen_US
dc.subjectSIVen_US
dc.titleClonal Analysis of Mucosal SIV-Specific CD8+ T Cell Responsesen_US
dc.typeThesis or Dissertationen_US
dash.embargo.until10000-01-01
thesis.degree.date2011en_US
thesis.degree.disciplineImmunologyen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberWelsh, Raymonden_US
dc.contributor.committeeMemberKaur, Amitinderen_US
dc.contributor.committeeMemberCantor, Harveyen_US


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