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dc.contributor.authorRosenberg, Charles Stephen
dc.date.accessioned2014-03-04T20:00:39Z
dc.date.available2014-03-04T20:00:39Z
dc.date.issued2011-05
dc.identifier.otherrosenberg_charles_s_201105_phd
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/rosenberg_charles_s_201105_phd
dc.identifier.urihttp://hdl.handle.net/10724/27287
dc.description.abstractTrypanosoma cruzi infection drives the expansion of parasite-specific CD8+ T cells recognizing peptide epitopes encoded by trans-sialidase (TS) gene family members. The immunodominance of TS is remarkable; with up to 40% of all CD8+ T cells expressing T cell receptors recognizing the dominant TSKB20 and sub-dominant TSKB18 epitopes, these responses are among the strongest documented in any infection. However, mice fail to completely clear T. cruzi and subsequently develop chronic disease despite generating such highly focused T cell responses. Since T. cruzi’s genome encodes thousands of variant TS genes, we questioned the significance of these TS-specific CD8+ T cells. To determine the necessity of TS-specific CD8+ T cells for control of T. cruzi infection, we epitope-tolerized mice by injections of synthetic peptide epitopes. Mice tolerized to either the dominant or sub-dominant epitope, or both simultaneously, had transiently increased parasite burden though ultimately controlled acute infection, likely due to the activities of CD8+ T cells specific for unidentified parasite-derived epitopes. We hypothesized that these normally non-dominant CD8+ T cells could mediate long-term control of T. cruzi, so we developed transgenic mice expressing the TSKB20 or TSKB18 peptides as self-antigen to ensure central tolerance of peptide-specific CD8+ T cells. Recapitulating our previous findings, mice deleted of CD8+ T cells specific for TSKB20, TSKB18 or both peptides, were resistant to T. cruzi and developed functional effector CD8+ T cells. Mice deleted of the normally dominant CD8+ T cells controlled T. cruzi infection, but developed chronic infection and similar disease as their wild-type littermates. Though immunodomination by TS-specific T cells interferes with the development of responses targeting other parasite-encoded epitopes, deletion of the described dominant CD8+ T cells did not appear to enhance protective immunity nor change the outcome of infection. These data do not support a major role for TS-epitope immunodominance as a mechanism exploited by T. cruzi to promote the parasite’s persistence in the immune host, however, the data do indicate that strong responses against these TS-derived epitopes are non-essential. Furthermore, immunodominance by a particular CD8+ T cell population does not predict a critical role for that population in the control of T. cruzi infection.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectTrypanosoma cruzi
dc.subjectChagas disease
dc.subjectCD8+ T cell
dc.subjectimmunodominance
dc.subjectimmune evasion
dc.subjecttolerance
dc.subjecttransgenic mouse
dc.titleThe role of CD8+ T cell immunodominance in control of experimental Trypanosoma cruzi infection
dc.typeDissertation
dc.description.degreePhD
dc.description.departmentMicrobiology
dc.description.majorMicrobiology
dc.description.advisorRick Tarleton
dc.description.committeeRick Tarleton
dc.description.committeeBoris Striepen
dc.description.committeeRobert Maier
dc.description.committeeDaniel G. Colley


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