PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of RORγ

Kurebayashi, Yutaka; Nagai, Shigenori; Ikejiri, Ai; Ohtani, Misato; Ichiyama, Kenji; Baba, Yukiko; Yamada, Taketo; Egami, Shohei; Hoshii, Takayuki; Hirao, Atsushi; Matsuda, Shinji; Koyasu, Shigeo

doi:10.1016/j.celrep.2012.02.007

Cited by 280 publications

(296 citation statements)

References 48 publications

Supporting

Mentioning

278

Contrasting

Order By: Relevance

“…Indeed, various drugs, leading to PI3K/Akt inhibition and Foxo1 activation, strongly decreased IL-17A-expressing CD4 T cells during in vitro differentiation of CD4 naive T cells into Th17 cells. These results are consistent with previous studies having shown that the PI3K/Akt/mTORC1 axis is important for Th17 differentiation (52,53). Our results also showed that this regulation of PI3K/Akt inhibitors on Th17 differentiation clearly occurs at the transcriptional level and that it can impact various Th17 genes simultaneously, as shown in this work for il-17a and il-17f genes (see Fig.…”

Section: Pharmacological Modulation Of Foxo1 Activity Controls Th17 Dsupporting

confidence: 82%

Foxo1 Is a T Cell–Intrinsic Inhibitor of the RORγt-Th17 Program

Laine

Martin

Luka

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell–intrinsic manner.

show abstract

Section: Pharmacological Modulation Of Foxo1 Activity Controls Th17 Dsupporting

confidence: 82%

Foxo1 Is a T Cell–Intrinsic Inhibitor of the RORγt-Th17 Program

Laine

Martin

Luka

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Thymic subsets based on CD4 and CD8 staining were similar between WT and Raptor-T-KO mice ( Fig. 2A), which is consistent with previous observations in Raptor f/fLckCre mice (19). Raptor protein level was obviously decreased in Raptor-T-KO thymocytes (Fig.…”

Section: Significancesupporting

confidence: 81%

“…Interestingly, mTORC1 has been demonstrated to control nuclear localization of multiple molecules both positively and negatively. It inhibits Lipin1 (a phosphatase for phosphatidic acid) and transcription factor EB nuclear translocation (36)(37)(38) but promotes RAR-related orphan receptor-γt nuclear accumulation (19). mTOR itself dynamically shuttles between the nucleus and cytoplasm in a rapamycin-dependent manner (39,40).…”

Section: Significancementioning

confidence: 99%

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Shin¹,

Wang

Deng

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The mechanisms that control invariant natural killer T (iNKT)-cell development and function are still poorly understood. The mechanistic or mammalian target of rapamycin (mTOR) integrates various environmental signals/cues to regulate cell growth, proliferation, metabolism, and survival. We report here that ablation of mTOR complex 1 (mTORC1) signaling by conditionally deleting Raptor causes severe defects in iNKT-cell development at early stages, leading to drastic reductions in iNKT-cell numbers in the thymus and periphery. In addition, loss of Raptor impairs iNKT-cell proliferation and production of cytokines upon α-galactosylceramide stimulation in vitro and in vivo, and inhibits liver inflammation in an iNKT cell-mediated hepatitis model. Furthermore, Raptor deficiency and rapamycin treatment lead to aberrant intracellular localization and functional impairment of promyelocytic leukemia zinc-finger, a transcription factor critical for iNKT-cell development and effector programs. Our findings define an essential role of mTORC1 to direct iNKT-cell lineage development and effector function.

show abstract

“…The PI3K/AKT pathway has been associated with Th17 cell development (38) and with IL-17 expression by CCR6 + human memory T cells (39). Thus, targeting MAPK/ERK along with the JAK/ PI3K/AKT pathways may be beneficial for inhibiting Th17-mediated bone loss.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

Azreq

Arseneault

Boisvert

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin α2β1 (CD49b), and IL-7 increases their adhesion to collagen via α2β1 integrin. In addition, coengagement of the two receptors in human Th17 cells cooperatively enhanced their IL-17 production and their osteoclastogenic function. The functional cooperation between IL-7R and α2β1 integrin involves activation of the JAK/PI3K/AKT (protein kinase B) and MAPK/ERK pathways. We also showed that IL-7–induced bone loss in vivo is associated with Th17 cell expansion. Moreover, blockade of α2β1 integrin with a neutralizing mAb inhibited IL-7–induced bone loss and osteoclast numbers by reducing Th17 cell numbers in the bone marrow and reducing the production of IL-17 and the receptor activator of NF-κB ligand. Thus, the cooperation between IL-7R and α2β1 integrin can represent an important pathogenic pathway in Th17-osteoclast function associated with inflammatory diseases.

show abstract

PI3K-Akt-mTORC1-S6K1/2 Axis Controls Th17 Differentiation by Regulating Gfi1 Expression and Nuclear Translocation of RORγ

Cited by 280 publications

References 48 publications

Foxo1 Is a T Cell–Intrinsic Inhibitor of the RORγt-Th17 Program

Foxo1 Is a T Cell–Intrinsic Inhibitor of the RORγt-Th17 Program

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

Contact Info

Product

Resources

About