Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways

Abstract

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt plays a critical role in regulating nTH17 cell development. While Akt and the downstream mTORC1–ARNT–HIFα axis were required for inducible TH17 (iTH17) cell generation in the periphery, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for nTH17 cell development. Moreover, Akt controlled TH17 subsets through distinct isoforms, as deletion of Akt2, but not Akt1, led to defective iTH17 cell generation. These findings reveal novel mechanisms regulating nTH17 cell development and previously unknown roles of Akt and mTOR in shaping T cell subsets.

Ikaros Sets the Potential for Th17 Lineage Gene Expression through Effects on Chromatin State in Early T Cell Development

“…Our finding that the proportion of thymic IL-17-producing T cells in Ikaros Ϫ/Ϫ mice is similar to that of wild type mice indicates that Ikaros exerts a more profound effect on inducible Th17 cell development and further supports the idea that although overlapping, some of mechanisms regulating nTh17 cell development appear to be distinct from that of Th17 antigen-induced differentiation in the periphery (54,55). Parallel disparities are also found in pathways that regulate nTreg and iTreg cells, where the expression of Helios, a member of the Ikaros transcription factor family, is uniquely expressed in thymic derived Treg cells (56).…”

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

“…It was reported recently that the PI3K-AKT-mTORC1-S6K axis positively regulates Th17 differentiation by promoting the nuclear translocation of RORγt (37,39). Here, we showed that pharmacologic inhibition of CaMK4 by KN-93 or genetic deletion of Camk4 in OT-II mice impairs the phosphorylation of S6K, indicating an importance of the CaMK4/ AKT/mTOR pathway in the regulation of Th17 differentiation.…”

“…The activation of mTORC1 enhances Th17 differentiation (37) and disruption of mTORC1 caused by deletion of Rheb or Raptor impairs Th17 differentiation (38,39). CaMKs, including CamK4, have been reported to modulate the AKT signaling pathway (40,41).…”

Rapamycin Induces Mitogen-activated Protein (MAP) Kinase Phosphatase-1 (MKP-1) Expression through Activation of Protein Kinase B and Mitogen-activated Protein Kinase Kinase Pathways

“…Despite the important role of AKT signaling and its regulation via mTORC1, mTORC2, and PI3K in various cellular processes including immune regulation, the differential roles of the AKT isoforms have not been well studied. Several recent studies indicate that AKT1 and AKT2 have differential roles in macrophages and T cell polarization (54,55). Although all three AKT isoforms share common upstream activators and some downstream substrates, it appears that they play distinct and non-redundant roles in biological processes.…”