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PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of

Yutaka Kurebayashi1, Shigenori Nagai, Ai Ikejiri

  • 1Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Tokyo 160-8582, Japan.

Cell Reports
|July 27, 2012
PubMed

Insights

The PI3K-Akt-mTORC1 pathway is crucial for T cell activation and survival. Its suppression impairs T helper 17 (Th17) cell differentiation by affecting key regulators like Gfi1 and RORγ.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Signaling

Background:

  • The PI3K-Akt-mTORC1 signaling pathway regulates critical cellular processes including T cell activation, survival, and proliferation.
  • CD4(+) T cell differentiation into various subsets, such as Th17 cells, is essential for adaptive immunity.

Purpose of the Study:

  • To investigate the role of the PI3K-Akt-mTORC1 signaling axis in the differentiation of Th17 cells.
  • To elucidate the downstream mechanisms by which this pathway influences Th17 cell development.

Main Methods:

  • Utilized genetic manipulation (p85α deletion, raptor deletion) and pharmacological inhibitors (PI3K/mTORC1 inhibitors) in vitro and in vivo.
  • Assessed Th17 differentiation, gene expression (Gfi1), and protein localization (S6K2, RORγ).

Main Results:

  • Suppression of the PI3K-Akt-mTORC1 axis significantly impaired Th17 differentiation in a S6K1/2-dependent manner.
  • Inhibition of this axis led to impaired downregulation of Gfi1, a negative regulator of Th17 differentiation.
  • S6K2 was found to be induced by the pathway, translocate to the nucleus, bind RORγ, and facilitate its nuclear import.

Conclusions:

  • The PI3K-Akt-mTORC1-S6K1/2 signaling axis plays a pivotal role in regulating Th17 cell differentiation.
  • This pathway influences Th17 differentiation through modulation of Gfi1 expression and RORγ nuclear translocation.

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