{"id":{"repo_id":"vcu","oai_identifier":"oai:scholarscompass.vcu.edu:etd-1371"},"canonical_url":"https://search.dev.ndltd.org/etd/vcu/oai:scholarscompass.vcu.edu:etd-1371","repository":{"repo_id":"vcu","name":"Virginia Commonwealth University","base_url":"https://scholarscompass.vcu.edu/do/oai/"},"display":{"title":"T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection","abstract":"The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection.","abstract_html":"The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection.","abstract_has_math":false,"creators":["Cobb, Dustin"],"institution":null,"degree_name":"Doctor of Philosophy","degree_level":"Dissertation","degree_discipline":"Microbiology & Immunology","degree_department":null,"school":null,"contributors":["Ronald B. Smeltz"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-05-23T07:00:00Z","date_published":"2012-05-23T07:00:00Z","updated_at":"2026-07-24T05:53:48Z","subjects":["T cells cytokines parasite T. cruzi IL-17","Medicine and Health Sciences"],"languages":[],"rights":["© The Author"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarscompass.vcu.edu/etd/372"],"render_values":[{"text":"https://scholarscompass.vcu.edu/etd/372","href":"https://scholarscompass.vcu.edu/etd/372","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.25772/RSGQ-0810","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Ronald B. Smeltz"]},{"key":"dc:creator","label":"Author","values":["Cobb, Dustin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2017-06-28T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Microbiology & Immunology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["T cells cytokines parasite T. cruzi IL-17","Medicine and Health Sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["© The Author"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.25772/RSGQ-0810","https://scholarscompass.vcu.edu/etd/372"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection."]},{"key":"dc:title","label":"Title","values":["T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection"]}]}],"canonical_facts":{"dc:contributor":["Ronald B. Smeltz"],"dc:creator":["Cobb, Dustin"],"dc:date.available":["2017-06-28T07:00:00Z"],"dc:description.abstract":["The human pathogen Trypanosoma cruzi is an intracellular parasite and the etiological agent of Chagas disease. Protective immune responses to T. cruzi are highly dependent on T helper 1 and CD8+ T cells which produce interferon-gamma. A deficiency in these responses has severe consequences on the ability to control infection. Our investigation into the role of the Th1 transcription factor, T-bet, during murine T. cruzi infection revealed that T-bet is required for resistance. Contrary to our expectations, T-bet was not required for the development of Th1 immunity during infection, as T-bet-deficient mice still developed interferon-gamma-producing T cells. However, T-bet was required to suppress the differentiation of Th17 cells and for the expansion of T. cruzi-specific CD8+ T cells. We first sought to determine the cause of reduced numbers of T. cruzi-specific CD8+ T cells in infected T-bet-deficient mice. First, we found that impaired migration or survival did not contribute to the low number of T. cruzi-specific CD8+ T cells. Secondly, we determined that reduced numbers of CD8+ T cells was not secondary to a defect in antigen-presenting cell activation or priming of CD8+ T cells. A recapitulation of defective expansion in mice with normal T-bet-expressing antigen-presenting cells demonstrated that T-bet expression in T cells was required. Thus, we determined that T-bet regulates the expansion of antigen-specific CD8+ T cells during T. cruzi infection in a T cell-intrinsic manner. Although it was evident T-bet had an integral role in suppressing the development of Th17 cells in response to infection with T. cruzi, several issues remained unclear. The first was the apparent lack of a negative regulatory effect of IFN-g/IFN-g-signaling on Th17 cells, which contradicted published reports. To clarify the role of IFN-g, we investigated the effect of IFN-g- or Stat-1-deficiency during T. cruzi infection. Surprisingly, IFN-g did not have a major role in up-regulating T-bet or for suppressing the development of Th17 responses, whereas Stat-1 was necessary for both. This was unexpected as Stat-1 is an IFN-g-inducible transcription factor, and its activation leads to T-bet induction. Thus, the T-bet-mediated inhibition of Th17 responses during T. cruzi infection is dependent on Stat-1, but not IFN-g. The final aim of this project was to identify the cytokines that negatively regulate Th17 differentiation in response to T. cruzi. We focused on the IL-12-family cytokines, IL-12 and IL-27, which are known to regulate T cell responses. Indeed, IL-12-deficient mice infected with T. cruzi developed a significant increase in Th17 cells similar to that observed in T-bet-deficient mice. Surprisingly, and in contrast to published results in other models, IL-27-deficient mice did not exhibit an increase in Th17 development. Our results demonstrate that IL-12, but not IL-27, is necessary for optimal T-bet expression and regulation of Th17 responses during T. cruzi infection."],"dc:identifier":["https://doi.org/10.25772/RSGQ-0810","https://scholarscompass.vcu.edu/etd/372"],"dc:rights":["© The Author"],"dc:subject":["T cells cytokines parasite T. cruzi IL-17","Medicine and Health Sciences"],"dc:title":["T-bet-dependent regulation of T cell responses during Trypanosoma cruzi infection"],"thesis:degree_discipline":["Microbiology & Immunology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy"]},"updated_at":"2026-07-24T05:53:48Z"}