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In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol
08:20

In Vitro Differentiation of Human CD4+FOXP3+ Induced Regulatory T Cells (iTregs) from Naïve CD4+ T Cells Using a TGF-β-containing Protocol

Published on: December 30, 2016

Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against

Taofeng Du1, Yasuhiro Nagai, Yan Xiao

  • 1Department of Pathology and Lab Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6082, USA.

Experimental and Molecular Pathology
|May 7, 2013
PubMed

Insights

Garcinol, a p300 inhibitor, causes p300 degradation, reducing regulatory T cell (Treg) function. This enhances anti-tumor antibody efficacy, suggesting p300 stability disruption for cancer therapy.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cancer Research

Background:

  • p300 is a key regulator of FOXP3 acetylation and function.
  • Histone acetyltransferase interactions influence FOXP3 activity.
  • Understanding p300's role in FOXP3 regulation is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the mechanism by which p300 regulates FOXP3 acetylation.
  • To explore the use of the natural p300 inhibitor, Garcinol, as a tool.
  • To assess the therapeutic potential of targeting p300 stability in cancer.

Main Methods:

  • Utilized Garcinol to study p300-FOXP3 interactions.
  • Investigated p300 degradation pathways (lysosome-dependent).
  • Assessed FOXP3 acetylation and degradation.
  • Evaluated the effect of Garcinol on regulatory T cell (Treg) function and anti-tumor activity in MMTV-neu transgenic models.

Main Results:

  • Garcinol induces p300 dissociation from FOXP3, leading to lysosome-dependent degradation.
  • p300 degradation results in decreased FOXP3 acetylation and subsequent degradation, independent of proteasomal activity.
  • Garcinol reduces Treg suppressive activity.
  • Garcinol enhances the in vivo anti-tumor efficacy of an anti-HER2 antibody.

Conclusions:

  • p300 plays a dual role in FOXP3 acetylation, with some sites repressing overall acetylation.
  • Garcinol effectively disrupts p300 stability, reducing Treg function.
  • Targeting p300 stability offers a promising strategy to limit Treg activity and enhance anti-tumor therapies in cancer.
Keywords:
AcetyltransferaseFOXP3GarcinolLysosome degradationRegulatory T cellsT(reg)p300

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