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 4

TSC1 deficiency in Foxp3+ Treg cells results in loss of Treg function under inflammatory condition.

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TSC1 deficiency in Foxp3+ Treg cells results in loss of Treg function un...
(A and B) Flow cytometric analysis (left), frequencies (right) of YFP expression (A), and absolute numbers of CD4+YFP+ T cells (B) from spleen or cLP of Foxp3YFPCreTsc1+/+ and Foxp3YFPCreTsc1f/f mice. (C) Flow cytometric analysis of Ki-67 expression in CD4+YFP+T cells (upper panel) and 7-AAD staining in CD4+YFP+T cells 48 hours after anti-CD3/CD28 stimulation (lower panel) in Foxp3YFPCreTsc1+/+ and Foxp3YFPCreTsc1f/f mice. Data are representative of (A and C) or compiled from (B) three independent experiments. Error bars indicate the mean ± SD by two-tailed, unpaired Student’s t test. (D) Rag1–/– mice were given sorted CD4+YFP+ (CD45.2+) Treg cells from Foxp3YFPCreTsc1+/+ or Foxp3YFPCreTsc1f/f mice, together with CD4+CD45RBhi (CD45.1+) T cells, or CD4+CD45RBhi (CD45.1+) T cells alone (None). Weight loss of individual mice was monitored every week for 12 weeks. (E–G) Ratios of CD4+CD45RBhigh (CD45.1+) to CD4+YFP+ (CD45.2+) Treg cells in the SP, LNs, MLNs, and cLP (E); absolute numbers of CD4+CD45.2+ T (Treg) cells (F); frequencies of the indicated cytokine-producing CD4+CD45.1+ T cells in spleen and cLP (G) in Rag1–/– recipient mice as in D 12 weeks after transfer. (H and I) Flow cytometric analysis of Foxp3+ expression in sorted CD4+CD45RBloYFP+ Treg cells before adoptive transfer (H) or 12 weeks after transfer (I) in Rag1–/– recipient mice as in D. Data are compiled from (D–G) or representative of (I) three independent experiments with two mice each. Error bars indicate the mean ± SD. *P < 0.05 and **P < 0.01 by two-tailed, unpaired Student’s t test.