TSC1 regulates the balance between effector and regulatory T cells
Yoon Park, … , Mitchell Kronenberg, Yun-Cai Liu
Yoon Park, … , Mitchell Kronenberg, Yun-Cai Liu
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5165-5178. https://doi.org/10.1172/JCI69751.
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Research Article

TSC1 regulates the balance between effector and regulatory T cells

Abstract

Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell–specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1–/– Foxp3+ Tregs. Elevated IL-17 production in Tsc1–/– Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.

Authors

Yoon Park, Hyung-Seung Jin, Justine Lopez, Chris Elly, Gisen Kim, Masako Murai, Mitchell Kronenberg, Yun-Cai Liu

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Figure 7

S6K1 knockdown in TSC1-deficient T cells leads to attenuated IL-17 production.

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S6K1 knockdown in TSC1-deficient T cells leads to attenuated IL-17 produ...
(A) Analysis of the phosphorylation status of the indicated downstream targets of TSC1. CD4+ T cells from WT or CD4creTsc1f/f mice were stimulated with anti-CD3/CD28 for the indicated time periods, and the cell lysates were subjected to immunoblotting with the indicated antibodies. (B) Analysis of GFP expression in peripheral blood from bone marrow chimeric mice 2Πmonths after reconstitution of control (shCON) or S6K1 or GRB10 shRNAs expressing WT or Cd4CreTsc1f/f bone marrow cells (upper panel). Immunoblot analysis of S6K1 and GRB10 was performed in sorted CD4+GFP+ T cells (lower panel). (C and D) Flow cytometric analysis (C, left panel), frequencies (C, right panel), or cytokine production (D) of Th17-polarized naive CD4+GFP+ T cells from bone marrow chimeric mice as in B. (E) Analysis of the phosphorylation status of S6K1 in CD4+YFP+ Treg cells. (F) Analysis of mAmetrine expression in peripheral blood from bone marrow chimeric mice 2 months after reconstitution of control or S6K1 shRNAs expressing Foxp3YFPCreTsc1+/+ or Foxp3YFPCreTsc1f/f bone marrow cells. (G) Cytokine production in CD4+YFP+mAmetrine+ T cells from bone marrow chimeric mice as in F was measured by Bio-Plex multicytokine assay 36 hours after stimulation with anti-CD3/CD28. Data are representative of (B, C, and F) or compiled from (D and G) three to five independent experiments. Error bars indicate the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001 by two-tailed, unpaired Student’s t test.