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 8

Double deletion of TSC1 and Foxo3a heightens Treg conversion to Th17-like cells.

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Double deletion of TSC1 and Foxo3a heightens Treg conversion to Th17-lik...
(A) Flow cytometric analysis of YFP and RFP expression in CD4+T cells of Foxp3YFPCreR26RFPTsc1+/+, Foxp3YFPCreR26RFPTsc1f/f, and Foxp3YFPCreR26RFPTsc1f/fFoxo3af/f mice. (B) Sorted CD4+RFP+YFP+ Treg cells (right) or CD4+RFP+YFP– ex-Treg cells (left) from the mice in A were stimulated with anti-CD3/CD28 for 36 hours. Cytokine production was measured by Bio-Plex multicytokine assay. (C) Sorted CD4+RFP+YFP+ Treg cells (right) or CD4+RFP+YFP– ex-Treg cells (left) from the mice in A were stimulated with anti-CD3/CD28 for 72 hours in the presence or absence of 250 nM rapamycin. Cytokine production was measured by Bio-Plex multicytokine assay. Data are representative of (A) or compiled from (B and C) three independent experiments. Error bars indicate the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by two-tailed, unpaired Student’s t test.