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Forkhead transcription factors FoxP1 and FoxP4 regulate T cell development and function.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Wiehagen, Karla Rose.
- Language:
- English
- Subjects (All):
- Immunology.
- 0982.
- Penn dissertations--Immunology.
- Immunology--Penn dissertations.
- Local Subjects:
- Penn dissertations--Immunology.
- Immunology--Penn dissertations.
- 0982.
- Physical Description:
- 194 pages
- Contained In:
- Dissertation Abstracts International 75-01B(E).
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- 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 naive 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.
- Notes:
- Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2013.
- Source: Dissertation Abstracts International, Volume: 75-01(E), Section: B.
- Adviser: Jonathan S. Maltzman.
- Local Notes:
- School code: 0175.
- ISBN:
- 9781303398896
- Access Restriction:
- Restricted for use by site license.
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