Modulation of HIV-1 replication and T cell activation by FoxP3

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  • March 21, 2019
Creator
  • Holmes, Derek Allan
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Regulatory T cells (Treg) are defined as the population of CD4+CD25+ that express the forkhead transcription factor family member FoxP3. Treg cells are characterized by the inability to produce IL-2 upon stimulation, defects in in vitro proliferation, and the ability to suppress effector T cell (Teff) activation. FoxP3 plays a crucial role in Treg function and is thought to be a factor required for the development and maintenance of Tregs. We first set out to describe the role of FoxP3 in the regulation of HIV LTR activation in Treg cells. Upon primary Treg infection with HIV-1 NL4-luciferase reporter virus, we observed increased transcription of the LTR. Similarly, primary T cells or Jurkat T cells transduced with retrovirus expressing Foxp3 showed a similar enhancement of HIV-1 LTR. We demonstrate that Foxp3 enhancement of LTR requires intact NF-κB binding sites, and FoxP3 expression is associated with increased binding of NF-κB at the core enhancer of HIV-1 LTR and differential histone acetylation of the LTR and IL-2 promoters. We demonstrate that FoxP3 expression in Jurkat T cells and primary Tregs inhibits global HDAC activity. Specifically, Foxp3 inhibits HDAC1 activity and this function requires the proline-rich domain. We show that FoxP3 is present in a large molecular weight complex with HDAC1, and interacts with HDAC1 in T cells. A point mutation in the forkhead domain that inhibits Foxp3 function in Tregs in vivo is unable to associate with and inhibit HDAC1 activity, suggesting the importance of FoxP3/HDAC1 interaction for HDAC1 inhibition. Finally, we demonstrate knockdown of HDAC1 inhibits FoxP3 regulation of IL-2 expression and HIV-1 LTR activity in T cells. Lastly, we report that FoxP3 interacts with the ATPase nucleosome remodeler Mi-2β in T cells. This interaction requires the zinc-finger domain, and FoxP3 expression is associated with a decreased binding of Mi-2β at the IL-2 promoter. We also demonstrate that knockdown of Mi-2β inhibits IL-2 expression, supporting a model for FoxP3-mediated repression of transcription through the removal of factors required for optimal gene expression. Thus, FoxP3 regulates gene expression at multiple levels, from transcription factor modulation to chromatin remodeling factor regulation.
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  • In Copyright
Advisor
  • Su, Lishan
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
Date uploaded
  • October 19, 2010

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