TY - JOUR
T1 - PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of RORγ
AU - Kurebayashi, Yutaka
AU - Nagai, Shigenori
AU - Ikejiri, Ai
AU - Ohtani, Masashi
AU - Ichiyama, Kenji
AU - Baba, Yukiko
AU - Yamada, Taketo
AU - Egami, Shohei
AU - Hoshii, Takayuki
AU - Hirao, Atsushi
AU - Matsuda, Satoshi
AU - Koyasu, Shigeo
N1 - Funding Information:
We thank S. Hori for OT-II x Rag2 −/− x Foxp3 sf mice; T. Nakano for Akt-mer tg mice; M Satake for anti-Runx Ab; A. Minowa and Y. Hirata for technical assistance; and K. Takei and K. Hidaka for animal care. This work was in part supported by CREST from the Japan Science and Technology Agency, a Grant-in-Aid for Young Scientist (B) (21790476 to S.N.), from the Japan Society for the Promotion of Science, a Grant-in-Aid from The Takeda Science Foundation (to S.N. and S.M.), a Grant-in-Aid from The Mochida Memorial Foundation for Medical and Pharmaceutical Research (to S.N.), a Health Sciences Research Grant for Research on Specific Diseases from the Ministry of Health, Labour and Welfare, Japan, a Grant-in-Aid for Scientific Research on Priority Areas (20060021 to S.N.), a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a private University, a grant for the Promotion of the Advancement of Education and Research in Graduate Schools, and a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. S.K. is a consultant for Medical and Biological Laboratories, Co. Ltd.
PY - 2012/3/19
Y1 - 2012/3/19
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2012.02.007
DO - 10.1016/j.celrep.2012.02.007
M3 - Article
C2 - 22832227
AN - SCOPUS:84861134382
VL - 1
SP - 360
EP - 373
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -