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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

Cutting edge: TGF-beta-induced expression of Foxp3 in T cells is mediated through inactivation of ERK

Xunrong Luo1, Qiang Zhang, Victoria Liu

  • 1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|February 23, 2008
PubMed

Insights

Transforming growth factor-beta (TGF-β) induces regulatory T cells via epigenetic changes. This study reveals that inhibiting ERK phosphorylation is key to TGF-β’s mechanism for Foxp3 expression and T cell regulation.

Area of Science:

  • Immunology
  • Epigenetics
  • Cellular Biology

Background:

  • Regulatory T cells (Tregs) are crucial for immune homeostasis.
  • Transforming growth factor-beta (TGF-β) is known to induce T regulatory cells through epigenetic mechanisms.
  • The precise molecular pathway of TGF-β-mediated Treg induction remains incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which TGF-β induces Foxp3 expression in T cells.
  • To investigate the role of Extracellular signal-Regulated Kinase (ERK) signaling in TGF-β-driven epigenetic regulation.
  • To determine if inhibiting ERK can replicate TGF-β's effects on T regulatory cell induction.

Main Methods:

  • CD4+CD25- T cells were treated with TGF-β during activation.
  • ERK phosphorylation was assessed following TGF-β treatment.
  • T cells were activated in the presence of a specific ERK inhibitor (UO126).
  • Expression of DNA methyltransferases (DNMTs) was analyzed after treatment with TGF-β or UO126.

Main Results:

  • TGF-β treatment transiently inhibited ERK phosphorylation, followed by Foxp3 induction.
  • Direct inhibition of ERK using UO126 also induced Foxp3 expression and suppressive function.
  • Both TGF-β and UO126 treatments led to down-regulation of DNMTs.
  • The observed DNMT down-regulation mimicked effects of demethylation agents.

Conclusions:

  • Epigenetic regulation of Foxp3 expression by TGF-β is mediated through the inactivation of ERK signaling.
  • ERK pathway inhibition is a critical step in TGF-β-induced T regulatory cell differentiation.
  • Targeting the ERK pathway offers a potential strategy for modulating T regulatory cell populations.

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