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The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.

Liu G, Yang K, Burns S, Shrestha S, Chi H - Nat. Immunol. (2010)

Bottom Line: Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance.Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P).Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

ABSTRACT
Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.

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SphK activity regulates T cell differentiation(a) Analysis fo Foxp3 expression in wild-type cells treated with various concentrations of S1P in a serum-free medium. (b) Analysis of SphK1 and SphK2 mRNA expression in cells activated in the absence or presence of TGF-β. Levels in naïve T cells were set to 1. (c) Analysis of Foxp3 expression after naïve T cells were pre-treated with DMS or SKI, and activated under iTreg conditions for 5 days. (d) Analysis of Foxp3 and CD25 expression in wild-type and S1P1-Tg naïve T cells were pre-treated with DMS (0.25 μM) or SKI (2.5 μM), and activated under iTreg conditions for 5 days. Data represent three independent experiments.
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Figure 8: SphK activity regulates T cell differentiation(a) Analysis fo Foxp3 expression in wild-type cells treated with various concentrations of S1P in a serum-free medium. (b) Analysis of SphK1 and SphK2 mRNA expression in cells activated in the absence or presence of TGF-β. Levels in naïve T cells were set to 1. (c) Analysis of Foxp3 expression after naïve T cells were pre-treated with DMS or SKI, and activated under iTreg conditions for 5 days. (d) Analysis of Foxp3 and CD25 expression in wild-type and S1P1-Tg naïve T cells were pre-treated with DMS (0.25 μM) or SKI (2.5 μM), and activated under iTreg conditions for 5 days. Data represent three independent experiments.

Mentions: Given an essential role of S1P1 in Treg cell differentiation, we explored mechanisms of S1P1 activation. Supplement of exogenous S1P to naïve T cells did not alter their differentiation into iTreg cells (Fig. 8a). We thus tested whether the endogenously produced S1P is involved. S1P is synthesized by one of the two sphingosine kinases (SphKs) on the substrate sphingosine34. In differentiating T cells, SphK1 was strongly upregulated by the treatment of TGF-β (Fig. 8b), suggesting the likely involvement of intrinsic SphK activity in iTreg cell generation. To test this hypothesis, we treated naïve T cells with N,N,-dimethylsphingosine (DMS) or sphingosine kinase inhibitor (SKI), two widely used inhibitors of SphK activity. Blocking SphK activity strongly upregulated Foxp3 induction (Fig. 8c). Treatment of S1P1-Tg cells with DMS or SKI restored their abilities to differentiate into iTreg cells (Fig. 8d). Similarly, blocking SphK activity considerably rectified the defects of S1P1-Tg cells in the reciprocal TH1 and Treg cell differentiation (Supplementary Fig. 13a). Thus, T cell differentiation mediated by S1P1 is dependent upon intrinsic SphKs, whose expression is upregulated by TGF-β as a feedback mechanism to limit TGF-β responses (Supplementary Fig. 13b).


The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.

Liu G, Yang K, Burns S, Shrestha S, Chi H - Nat. Immunol. (2010)

SphK activity regulates T cell differentiation(a) Analysis fo Foxp3 expression in wild-type cells treated with various concentrations of S1P in a serum-free medium. (b) Analysis of SphK1 and SphK2 mRNA expression in cells activated in the absence or presence of TGF-β. Levels in naïve T cells were set to 1. (c) Analysis of Foxp3 expression after naïve T cells were pre-treated with DMS or SKI, and activated under iTreg conditions for 5 days. (d) Analysis of Foxp3 and CD25 expression in wild-type and S1P1-Tg naïve T cells were pre-treated with DMS (0.25 μM) or SKI (2.5 μM), and activated under iTreg conditions for 5 days. Data represent three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2958252&req=5

Figure 8: SphK activity regulates T cell differentiation(a) Analysis fo Foxp3 expression in wild-type cells treated with various concentrations of S1P in a serum-free medium. (b) Analysis of SphK1 and SphK2 mRNA expression in cells activated in the absence or presence of TGF-β. Levels in naïve T cells were set to 1. (c) Analysis of Foxp3 expression after naïve T cells were pre-treated with DMS or SKI, and activated under iTreg conditions for 5 days. (d) Analysis of Foxp3 and CD25 expression in wild-type and S1P1-Tg naïve T cells were pre-treated with DMS (0.25 μM) or SKI (2.5 μM), and activated under iTreg conditions for 5 days. Data represent three independent experiments.
Mentions: Given an essential role of S1P1 in Treg cell differentiation, we explored mechanisms of S1P1 activation. Supplement of exogenous S1P to naïve T cells did not alter their differentiation into iTreg cells (Fig. 8a). We thus tested whether the endogenously produced S1P is involved. S1P is synthesized by one of the two sphingosine kinases (SphKs) on the substrate sphingosine34. In differentiating T cells, SphK1 was strongly upregulated by the treatment of TGF-β (Fig. 8b), suggesting the likely involvement of intrinsic SphK activity in iTreg cell generation. To test this hypothesis, we treated naïve T cells with N,N,-dimethylsphingosine (DMS) or sphingosine kinase inhibitor (SKI), two widely used inhibitors of SphK activity. Blocking SphK activity strongly upregulated Foxp3 induction (Fig. 8c). Treatment of S1P1-Tg cells with DMS or SKI restored their abilities to differentiate into iTreg cells (Fig. 8d). Similarly, blocking SphK activity considerably rectified the defects of S1P1-Tg cells in the reciprocal TH1 and Treg cell differentiation (Supplementary Fig. 13a). Thus, T cell differentiation mediated by S1P1 is dependent upon intrinsic SphKs, whose expression is upregulated by TGF-β as a feedback mechanism to limit TGF-β responses (Supplementary Fig. 13b).

Bottom Line: Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance.Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P).Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

ABSTRACT
Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.

Show MeSH
Related in: MedlinePlus