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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
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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

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Protein kinase C-θ inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway

Jian Ma1, Yan Ding, Xianfeng Fang

  • 1Division of Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|April 28, 2012
PubMed

Insights

Protein kinase C theta (PKC-θ) inhibits regulatory T cell differentiation through an AKT-Foxo1/3A pathway. This finding reveals how PKC-θ balances effector and regulatory T cell populations in immune responses.

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • Protein kinase C theta (PKC-θ) is a key molecule in T cell receptor (TCR) signaling.
  • PKC-θ promotes naive T cell differentiation into inflammatory effector T cells.

Purpose of the Study:

  • To investigate the role of PKC-θ in inducible regulatory T cell (iTreg) differentiation.
  • To elucidate the molecular pathway by which PKC-θ influences iTreg development.

Main Methods:

  • Utilized PKC-θ knockout (PKC-θ(-/-)) T cells and wild-type T cells.
  • Employed PKC-θ inhibitors and activators, including PMA and CD28 crosslinking.
  • Manipulated AKT kinase activity and its downstream targets, Foxo1 and Foxo3a, through genetic and pharmacological means.

Main Results:

  • PKC-θ deficiency or inhibition enhanced TGF-β-induced iTreg differentiation.
  • PKC-θ activation, via PMA or CD28 crosslinking, inhibited iTreg differentiation.
  • PKC-θ(-/-) T cells showed reduced AKT activity; restoring AKT activity in these cells inhibited iTreg differentiation.
  • Modulation of Foxo1/3a expression levels in PKC-θ(-/-) T cells directly affected iTreg differentiation.

Conclusions:

  • PKC-θ signaling inhibits iTreg differentiation via the AKT-Foxo1/3A pathway.
  • PKC-θ plays a critical role in regulating the balance between effector T cells and regulatory T cells.
  • This mechanism provides a novel target for controlling T cell-mediated immune responses.

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