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.

Naive CD4(+) T cells are activated by antigen-presenting cells (APCs) and differentiate into distinct types of helper T (T(h)) cells in the lymph node or spleen. Oxygen (O(2)) tension is generally low in these secondary lymphoid tissues compared with the bloodstream or atmosphere. However, the effect of changes in O(2) concentration on the differentiation of T(h) cells remains unclear. Here, we established a novel model of T(h)-cell differentiation, which mimics physiological O(2) conditions. We primed naive CD4(+) T cells under 5% O(2), which has been observed in the lymph node or spleen and reoxygenated under normoxia that mimicked the O(2) concentration in blood. In this model, the differentiation of T(h)17 cells, but not T(h)1 or iTreg cells, was enhanced. Under the condition of 5% O(2), mammalian target of rapamycin complex 1 (mTORC1) was activated and led to the stabilization of hypoxia-inducible factor 1α (HIF-1α) in T(h)17 cells. The activation of mTORC1 and the acceleration of T(h)17-cell differentiation, which occurred when cells were primed under 5% O(2), were not observed in the absence of HIF-1α but were accelerated in the absence of von Hippel-Lindau tumor suppressor protein (vHL), a factor critical for HIF-1α degradation. Thus, a positive feedback loop between HIF-1α and mTORC1 induced by hypoxia followed by reoxygenation accelerates T(h)17-cell differentiation.

IL-17-producing T helper (Th17) cells comprise a distinct Th subset involved in epithelial cell- and neutrophil-mediated immune responses against extracellular microbes. At the same time, Th17 cells play significant roles in the development of autoimmune diseases including rheumatoid arthritis and multiple sclerosis. Since the identification of Th17 cells approximately a decade ago, the molecular mechanisms of their differentiation have been intensively studied and a number of signaling cascades and transcription factors have been shown to be involved. Here, we review the current knowledge regarding the function of Th17 cells in vivo as well as several key concepts for the molecular mechanisms of Th17 differentiation. We also discuss the emerging roles of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) in the differentiation of Th17 cells.