PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of RORγ

The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferation of CD4+ T cells upon stimulation through TCR and CD28. Here, we demonstrate that the suppression of this axis by deletion of p85α or PI3K/mTORC1 inhibitors as well as T cell-specific deletion of raptor, an essential component of mTORC1, impairs Th17 differentiation in vitro and in vivo in a S6K1/2-dependent fashion. Inhibition of PI3K-Akt-mTORC1-S6K1 axis impairs the downregulation of Gfi1, a negative regulator of Th17 differentiation. Furthermore, we demonstrate that S6K2, a nuclear counterpart of S6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORγ, and carries RORγ to the nucleus. These results point toward a pivotal role of PI3K-Akt-mTORC1-S6K1/2 axis in Th17 differentiation. [Display omitted] ► PI3K-Akt-mTORC1 axis controls Th17 (IL-17 secreting T helper) cell differentiation ► This involves downregulation of Gfi1, a negative regulator of Th17 differentiation ► PI3K-Akt-mTORC1 axis also accelerates nuclear translocation of RORg ► mTORC1 inhibition blocks Th17 differentiation in vivo The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferation of CD4+ T cells upon stimulation through TCR and CD28. Koyasu and colleagues demonstrate that this axis positively regulates Th17 differentiation in a fashion dependent upon the ribosomal protein S6 kinase (S6K1/2). Inhibition of the PI3K-Akt-mTORC1-S6K1 axis impairs downregulation of Gfi-1, a negative regulator of Th17 differentiation. Furthermore, the authors show that S6K2, a nuclear counterpart of S6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORγ, and carries RORγ into the nucleus.