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Title page for ETD etd-07222013-141402

Type of Document Dissertation
Author Williams, Christopher Lawrence
URN etd-07222013-141402
Title Instability of an epigenetic mark: T-bet and STAT4 influence the symmetry and plasticity of DNA methylation at the IFN-γ promoter in effector and memory Th2 lymphocytes
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Sebastian Joyce Committee Chair
Earl Ruley Committee Member
James W. Thomas Committee Member
Mark Boothby Committee Member
Richard O'Brien Committee Member
  • CD4 T cell memory
  • DNA methylation
  • T-bet
  • STAT4
  • Interferon gamma
Date of Defense 2013-06-24
Availability unrestricted
CD4+ T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN-γ. IL-4–producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to cells producing both IFN-γ and IL-4. We now show that this flexibility of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization. We also demonstrate that flexible expression of Ifng requires the transcription factor STAT4, along with T-bet. Surprisingly, loss of either STAT4 or T-bet increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation.
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