{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/32731"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/32731","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"Forkhead Transcription Factors Foxp1 and Foxp4 Regulate T Cell Development and Function","abstract":"Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of native T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins. In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage. T cell development and homeostasis are normal in the absence of Foxp4. Despite effective control of infection with Toxoplasma gondii or acute Lymphocytic choriomeningitis virus in vivo, cytokine production during antigen-specific rechallenge is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for normal memory T cell recall responses to antigen in acutely or chronically infected mice. Next we determined whether FoxP family members compensate for one another in Foxp1- or Foxp4-knockout models. We utilized a similar CD4Cre approach to delete both Foxp1 and Foxp4 in T cells. Foxp1/4-deficient T cells exhibit abnormal thymic development and T cell receptor signaling. Loss of Foxp1/4 results in significantly reduced T cell numbers, and altered T cell effector function, reminiscent of Foxp1-deficient T cells. Lastly, we examined the functions of Foxp1/4 in Foxp3+ regulatory T cells (Tregs). Tregs are critical for prevention of autoimmunity and controlling immune responses during infection. While conditional deletion of either Foxp1 or Foxp4 in T cells has little effect on Tregs, combined deletion results in abnormal Treg generation. Foxp1/4-deficient Tregs exhibited significant defects in both development and homeostasis. Under competitive conditions, double-deficient Tregs are at a significant developmental disadvantage relative to wild-type competitors. Furthermore, Foxp1/4-deficient Tregs exhibit impaired cytokine-induced STAT5 phosphorylation and reduced expression of Foxp3, suggesting Foxp1/4 is required for normal Treg generation. Together, these findings demonstrate that the FoxP family regulates multiple facets of T cell development and function, and actively contributes to the maintenance of immunological tolerance.","abstract_html":"Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of native T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins. In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage. T cell development and homeostasis are normal in the absence of Foxp4. Despite effective control of infection with Toxoplasma gondii or acute Lymphocytic choriomeningitis virus in vivo, cytokine production during antigen-specific rechallenge is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for normal memory T cell recall responses to antigen in acutely or chronically infected mice. Next we determined whether FoxP family members compensate for one another in Foxp1- or Foxp4-knockout models. We utilized a similar CD4Cre approach to delete both Foxp1 and Foxp4 in T cells. Foxp1/4-deficient T cells exhibit abnormal thymic development and T cell receptor signaling. Loss of Foxp1/4 results in significantly reduced T cell numbers, and altered T cell effector function, reminiscent of Foxp1-deficient T cells. Lastly, we examined the functions of Foxp1/4 in Foxp3+ regulatory T cells (Tregs). Tregs are critical for prevention of autoimmunity and controlling immune responses during infection. While conditional deletion of either Foxp1 or Foxp4 in T cells has little effect on Tregs, combined deletion results in abnormal Treg generation. Foxp1/4-deficient Tregs exhibited significant defects in both development and homeostasis. Under competitive conditions, double-deficient Tregs are at a significant developmental disadvantage relative to wild-type competitors. Furthermore, Foxp1/4-deficient Tregs exhibit impaired cytokine-induced STAT5 phosphorylation and reduced expression of Foxp3, suggesting Foxp1/4 is required for normal Treg generation. Together, these findings demonstrate that the FoxP family regulates multiple facets of T cell development and function, and actively contributes to the maintenance of immunological tolerance.","abstract_has_math":false,"creators":["Wiehagen, Karla Rose"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Jonathan S. Maltzman"],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-01-01","date_published":"2013-01-01","updated_at":"2026-07-24T03:45:26Z","subjects":[],"languages":["en"],"rights":["Karla Rose Wiehagen"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/32731","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Jonathan S. 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Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of native T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins. In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage. T cell development and homeostasis are normal in the absence of Foxp4. Despite effective control of infection with Toxoplasma gondii or acute Lymphocytic choriomeningitis virus in vivo, cytokine production during antigen-specific rechallenge is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for normal memory T cell recall responses to antigen in acutely or chronically infected mice. Next we determined whether FoxP family members compensate for one another in Foxp1- or Foxp4-knockout models. We utilized a similar CD4Cre approach to delete both Foxp1 and Foxp4 in T cells. Foxp1/4-deficient T cells exhibit abnormal thymic development and T cell receptor signaling. Loss of Foxp1/4 results in significantly reduced T cell numbers, and altered T cell effector function, reminiscent of Foxp1-deficient T cells. Lastly, we examined the functions of Foxp1/4 in Foxp3+ regulatory T cells (Tregs). Tregs are critical for prevention of autoimmunity and controlling immune responses during infection. While conditional deletion of either Foxp1 or Foxp4 in T cells has little effect on Tregs, combined deletion results in abnormal Treg generation. Foxp1/4-deficient Tregs exhibited significant defects in both development and homeostasis. Under competitive conditions, double-deficient Tregs are at a significant developmental disadvantage relative to wild-type competitors. Furthermore, Foxp1/4-deficient Tregs exhibit impaired cytokine-induced STAT5 phosphorylation and reduced expression of Foxp3, suggesting Foxp1/4 is required for normal Treg generation. Together, these findings demonstrate that the FoxP family regulates multiple facets of T cell development and function, and actively contributes to the maintenance of immunological tolerance."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy (PhD)"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Forkhead Transcription Factors Foxp1 and Foxp4 Regulate T Cell Development and Function"]}]}],"canonical_facts":{"dc:contributor.advisor":["Jonathan S. Maltzman"],"dc:creator":["Wiehagen, Karla Rose"],"dc:date":["2023-05-17T09:33:19.000"],"dc:date.accessioned":["2023-05-22T18:53:31Z"],"dc:date.available":["2014-07-29T00:00:00Z"],"dc:date.issued":["2013-01-01"],"dc:description.abstract":["Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of native T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins. In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage. T cell development and homeostasis are normal in the absence of Foxp4. Despite effective control of infection with Toxoplasma gondii or acute Lymphocytic choriomeningitis virus in vivo, cytokine production during antigen-specific rechallenge is reduced in the absence of Foxp4. We conclude that Foxp4 is dispensable for T cell development, but necessary for normal memory T cell recall responses to antigen in acutely or chronically infected mice. Next we determined whether FoxP family members compensate for one another in Foxp1- or Foxp4-knockout models. We utilized a similar CD4Cre approach to delete both Foxp1 and Foxp4 in T cells. Foxp1/4-deficient T cells exhibit abnormal thymic development and T cell receptor signaling. Loss of Foxp1/4 results in significantly reduced T cell numbers, and altered T cell effector function, reminiscent of Foxp1-deficient T cells. Lastly, we examined the functions of Foxp1/4 in Foxp3+ regulatory T cells (Tregs). Tregs are critical for prevention of autoimmunity and controlling immune responses during infection. While conditional deletion of either Foxp1 or Foxp4 in T cells has little effect on Tregs, combined deletion results in abnormal Treg generation. Foxp1/4-deficient Tregs exhibited significant defects in both development and homeostasis. Under competitive conditions, double-deficient Tregs are at a significant developmental disadvantage relative to wild-type competitors. Furthermore, Foxp1/4-deficient Tregs exhibit impaired cytokine-induced STAT5 phosphorylation and reduced expression of Foxp3, suggesting Foxp1/4 is required for normal Treg generation. Together, these findings demonstrate that the FoxP family regulates multiple facets of T cell development and function, and actively contributes to the maintenance of immunological tolerance."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/32731"],"dc:language":["en"],"dc:rights":["Karla Rose Wiehagen"],"dc:title":["Forkhead Transcription Factors Foxp1 and Foxp4 Regulate T Cell Development and Function"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:45:26Z"}