{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/70159"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/70159","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"The State of T Cell Immunity against Influenza Virus in Humans and Exploration of Potential Strategies to Enhance Cell-Mediated Protection from Influenza Infection","abstract":"There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine.","abstract_html":"There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine.","abstract_has_math":false,"creators":["Wagar, Lisa"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Immunology","school":null,"contributors":[],"advisors":["Watts, Tania"],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-11","date_published":"2013-11","updated_at":"2026-07-27T21:28:09Z","subjects":["influenza","CD8 T cells","immune memory","vaccination","immune aging","human immunology"],"languages":["en_ca"],"rights":["Attribution-ShareAlike 2.5 Canada"],"rights_urls":["http://creativecommons.org/licenses/by-sa/2.5/ca/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/70159","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Watts, Tania"]},{"key":"dc:contributor.department","label":"Department","values":["Immunology"]},{"key":"dc:creator","label":"Author","values":["Wagar, Lisa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-11"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2015-11-16T16:29:28Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["WITHHELD_TWO_YEAR","2015-11-16T16:29:28Z"]},{"key":"dc:date.issued","label":"Date","values":["2013-11"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["influenza","CD8 T cells","immune memory","vaccination","immune aging","human immunology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-ShareAlike 2.5 Canada"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-sa/2.5/ca/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/70159"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["The State of T Cell Immunity against Influenza Virus in Humans and Exploration of Potential Strategies to Enhance Cell-Mediated Protection from Influenza Infection"]}]}],"canonical_facts":{"dc:contributor.advisor":["Watts, Tania"],"dc:contributor.department":["Immunology"],"dc:creator":["Wagar, Lisa"],"dc:date":["2013-11"],"dc:date.accessioned":["2015-11-16T16:29:28Z"],"dc:date.available":["WITHHELD_TWO_YEAR","2015-11-16T16:29:28Z"],"dc:date.issued":["2013-11"],"dc:description.abstract":["There is great interest in developing a broadly efficacious influenza vaccine, as current antibody-eliciting formulations require annual re-immunization and are not effective in those most susceptible to influenza-related mortality. In contrast to antibody responses, influenza-specific CD8 T cells are broadly cross-reactive between strains, and previous reports have indicated that cellular immunity is a better correlate of protection than neutralizing antibody titers. However, little is known about the state of influenza-specific cellular immunity in humans. To address this, we examined the CD8 T cell responses of humans of different age, vaccination, and infection history to determine whether any of these factors alter the functionality of cell-mediated immune memory. We identified distinct phenotypic changes in influenza-specific T cells from older subjects, which were predictive of their antibody responses upon influenza vaccination. However, the inactivated vaccine itself had no discernible immediate or persisting effects on influenza-specific CD8 T cell responses of young or old humans. Furthermore, adults (mean age 44) who acquired natural influenza infections of the 2009 pandemic strain also had similar influenza-specific CD8 T cell responses 8-10 months after infection compared to controls. From these results, we concluded that influenza infection and vaccination do not result in significant long-term boosting of pre-existing influenza-specific CD8 T cell responses and that a lifetime of acute influenza infections can result in a senescent phenotype similar to chronically stimulated dysfunctional cells. These data suggested that boosting functional influenza-specific CD8 T cells in middle age that endure into old age could enhance protection in the elderly. To test this, we evaluated a murine prime/boost model using the 4-1BB costimulatory pathway to induce persisting CD8 T cell responses. 4-1BBL signals during boost immunization resulted in superior numbers and function of persisting influenza-specific CD8 T cells. Since TRAF1, an adaptor molecule for 4-1BB signaling, is polymorphic in humans, a preliminary investigation was undertaken to assess the effect of TRAF1 polymorphisms on T cell responses. Although a range of TRAF1 expression was detected, all donors exhibited enhanced T cell activation with anti-4-1BB, suggesting that targeting this pathway has therapeutic potential in a human T cell-stimulating influenza vaccine."],"dc:description.degree":["PhD"],"dc:identifier.uri":["http://hdl.handle.net/1807/70159"],"dc:language.iso":["en_ca"],"dc:rights":["Attribution-ShareAlike 2.5 Canada"],"dc:rights.uri":["http://creativecommons.org/licenses/by-sa/2.5/ca/"],"dc:subject":["influenza","CD8 T cells","immune memory","vaccination","immune aging","human immunology"],"dc:title":["The State of T Cell Immunity against Influenza Virus in Humans and Exploration of Potential Strategies to Enhance Cell-Mediated Protection from Influenza Infection"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:09Z"}