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 has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1–ARNT–HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.
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Acknowledgements
We thank B. Stiles (University of Southern California) for tissue from Akt1−/− mice; members of the Stem Cell and Xenotransplantation Core facility of the University of Pennsylvania for assistance with obtaining previously collected and de-identified human fetal thymic tissue; B. Monks for invaluable technical assistance and animal husbandry; L. Dipilato (University of Pennsylvania) for Akt inhibitors and helpful suggestions; S. Carty and T. Kambayashi for critically reading the manuscript; J. Stadanlick for editorial assistance; and members of the Koretzky and Jordan laboratories for helpful discussions. This work was supported by grants from US National Institutes of Health R01 DK56886 (M.J.B.), 5K01AR52802 (M.S.J.) and R37GM053256 (G.A.K.).
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J.S.K. designed the research, did experiments and wrote the manuscript; T.S., L.B.B. and M.G. performed experiments; A.T.W., K.N.P. and J.D.P. provided the Rhebfl/fl CD4-Cre and Rictorfl/fl CD4-Cre tissue; N.S. and B.L.K. provided the Arntfl/fl Vav1-Cre tissue; C.T.L. and M.O.L. provided the Foxo1ΔTFoxo3fl/fl CD4-Cre tissue; W.H. and J.C.R. provided the myr-Akt tissue; M.J.B. provided Akt1−/− and Akt2−/− mice and helpful suggestions; and M.S.J. and G.A.K. oversaw research and helped write the manuscript.
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Kim, J., Sklarz, T., Banks, L. et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 14, 611–618 (2013). https://doi.org/10.1038/ni.2607
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DOI: https://doi.org/10.1038/ni.2607
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