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

Jiyeon S. Kim; Tammarah Sklarz; Lauren B. Banks; Mercy Gohil; Adam T. Waickman; Nicolas Skuli; Bryan L. Krock; Chong T. Luo; Weihong Hu; Kristin N. Pollizzi; Ming O. Li; Jeffrey C. Rathmell; Morris J. Birnbaum; Jonathan D. Powell; Martha S. Jordan; Gary A. Koretzky

doi:10.1038/ni.2607

Natural and inducible T_H17 cells are regulated differently by Akt and mTOR pathways

Jiyeon S. Kim, Tammarah Sklarz, Lauren B. Banks, Mercy Gohil, Adam T. Waickman, Nicolas Skuli, Bryan L. Krock, Chong T. Luo, Weihong Hu, Kristin N. Pollizzi, Ming O. Li, Jeffrey C. Rathmell, Morris J. Birnbaum, Jonathan D. Powell, Martha S. Jordan, Gary A. Koretzky

Research output: Contribution to journal › Article › peer-review

Abstract

Natural T helper 17 (nT_H17) 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 nT_H17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible T_H17 (iT_H17) cells, nT _H17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nT_H17 cells. Moreover, distinct isoforms of Akt controlled the generation of T _H17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iT_H17 cells. These findings define mechanisms regulating nT_H17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.

Original language	English (US)
Pages (from-to)	611-618
Number of pages	8
Journal	Nature Immunology
Volume	14
Issue number	6
DOIs	https://doi.org/10.1038/ni.2607
State	Published - Jun 2013
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni.2607

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Kim, J. S., Sklarz, T., Banks, L. B., Gohil, M., Waickman, A. T., Skuli, N., Krock, B. L., Luo, C. T., Hu, W., Pollizzi, K. N., Li, M. O., Rathmell, J. C., Birnbaum, M. J., Powell, J. D., Jordan, M. S., & Koretzky, G. A. (2013). Natural and inducible T_H17 cells are regulated differently by Akt and mTOR pathways. Nature Immunology, 14(6), 611-618. https://doi.org/10.1038/ni.2607

Natural and inducible T_H17 cells are regulated differently by Akt and mTOR pathways. / Kim, Jiyeon S.; Sklarz, Tammarah; Banks, Lauren B.; Gohil, Mercy; Waickman, Adam T.; Skuli, Nicolas; Krock, Bryan L.; Luo, Chong T.; Hu, Weihong; Pollizzi, Kristin N.; Li, Ming O.; Rathmell, Jeffrey C.; Birnbaum, Morris J.; Powell, Jonathan D.; Jordan, Martha S.; Koretzky, Gary A.

In: Nature Immunology, Vol. 14, No. 6, 06.2013, p. 611-618.

Research output: Contribution to journal › Article › peer-review

Kim, Jiyeon S. ; Sklarz, Tammarah ; Banks, Lauren B. ; Gohil, Mercy ; Waickman, Adam T. ; Skuli, Nicolas ; Krock, Bryan L. ; Luo, Chong T. ; Hu, Weihong ; Pollizzi, Kristin N. ; Li, Ming O. ; Rathmell, Jeffrey C. ; Birnbaum, Morris J. ; Powell, Jonathan D. ; Jordan, Martha S. ; Koretzky, Gary A. / Natural and inducible T_H17 cells are regulated differently by Akt and mTOR pathways. In: Nature Immunology. 2013 ; Vol. 14, No. 6. pp. 611-618.

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title = "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 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, nT H17 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 T H17 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.",

author = "Kim, {Jiyeon S.} and Tammarah Sklarz and Banks, {Lauren B.} and Mercy Gohil and Waickman, {Adam T.} and Nicolas Skuli and Krock, {Bryan L.} and Luo, {Chong T.} and Weihong Hu and Pollizzi, {Kristin N.} and Li, {Ming O.} and Rathmell, {Jeffrey C.} and Birnbaum, {Morris J.} and Powell, {Jonathan D.} and Jordan, {Martha S.} and Koretzky, {Gary A.}",

note = "Funding Information: 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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T1 - Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways

AU - Kim, Jiyeon S.

AU - Sklarz, Tammarah

AU - Banks, Lauren B.

AU - Gohil, Mercy

AU - Waickman, Adam T.

AU - Skuli, Nicolas

AU - Krock, Bryan L.

AU - Luo, Chong T.

AU - Hu, Weihong

AU - Pollizzi, Kristin N.

AU - Li, Ming O.

AU - Rathmell, Jeffrey C.

AU - Birnbaum, Morris J.

AU - Powell, Jonathan D.

AU - Jordan, Martha S.

AU - Koretzky, Gary A.

N1 - Funding Information: 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.).

PY - 2013/6

Y1 - 2013/6

N2 - 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, nT H17 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 T H17 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.

AB - 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, nT H17 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 T H17 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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Natural and inducible T_H17 cells are regulated differently by Akt and mTOR pathways

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