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 December 2, 2013; First 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 1

TSC1 function in T cells preserves intestinal homeostasis.

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TSC1 function in T cells preserves intestinal homeostasis. (A) H&E s...
(A) H&E staining and histological scores of colon and liver tissue sections from 6-month-old mice. Original magnification, ×100. Data are representative of (left) and compiled from (right) 6 mice. Error bars indicate the mean ± SD. *P < 0.05 by two-tailed, unpaired Student’s t test. (B) Overview of DSS-induced chronic colitis model. Mice were administrated 2% DSS for 7 days followed by water and were analyzed up to 4 weeks later. (C) Body weight changes in WT and Cd4CreTsc1f/f mice after DSS treatment. Weight loss of individual mice was monitored every 2 days. Data are compiled from three independent experiments with three mice each. Error bars indicate the mean ± SD. *P < 0.05 by two-tailed, unpaired Student’s t test. (D–F) Colon length (D); photograph of representative spleen (SP) and mesenteric lymph nodes (MLNs) (E); H&E staining and histology scores of colon (F). Original magnification, ×100 (F). (G) Flow cytometric analysis of cytokine production (left) and frequencies (right) in colonic lamina propria (cLP) and splenic (SP) CD4+ T cells. Cells were obtained from WT and Cd4CreTsc1f/f mice 3 weeks after DSS removal (day 28) and restimulated in vitro. Data are compiled from (D) or representative of (E–G) three independent experiments. Each symbol represents an individual mouse (n = 5–6). 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.