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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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S1P1-mTOR axis is targeted by FTY720 and rapamycin(a) Kinetics of mTOR activation in wild-type and S1P1-Tg cells stimulated for various times. (b) Analysis of Smad3 and S6 activation in wild-type and S1P1-Tg cells treated with FTY720 and rapamycin and activated for 2 days. (c,d) Analysis of Foxp3 (c) and IFN-γ expression (d) in OT-II;Rag1−/− and S1P1-Tg;OT-II;Rag1−/− mice fed with Ova in the drinking water for 5 days, accompanied by daily FTY720 (1 mg/kg) or rapamycin (3 mg/kg) treatment. (e) Analysis of Foxp3 expression in thymic CD4SP cells from wild-type and S1P1-Tg mice treated daily with FTY720 and rapamycin for a total of 5 days. Data represent three independent experiments. (f) Induction of Foxp3 in thymic Treg precursors from wild-type and S1pr1flox/flox;Cd4-Cre mice stimulated with IL-2 (50 U/ml) in the presence of SIS3.
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Figure 7: S1P1-mTOR axis is targeted by FTY720 and rapamycin(a) Kinetics of mTOR activation in wild-type and S1P1-Tg cells stimulated for various times. (b) Analysis of Smad3 and S6 activation in wild-type and S1P1-Tg cells treated with FTY720 and rapamycin and activated for 2 days. (c,d) Analysis of Foxp3 (c) and IFN-γ expression (d) in OT-II;Rag1−/− and S1P1-Tg;OT-II;Rag1−/− mice fed with Ova in the drinking water for 5 days, accompanied by daily FTY720 (1 mg/kg) or rapamycin (3 mg/kg) treatment. (e) Analysis of Foxp3 expression in thymic CD4SP cells from wild-type and S1P1-Tg mice treated daily with FTY720 and rapamycin for a total of 5 days. Data represent three independent experiments. (f) Induction of Foxp3 in thymic Treg precursors from wild-type and S1pr1flox/flox;Cd4-Cre mice stimulated with IL-2 (50 U/ml) in the presence of SIS3.

Mentions: We further explored the signaling pathway utilized by S1P1 to antagonize TGF-β-Smad3 signaling. The Akt-mTOR pathway has recently been shown to restrain iTreg generation28–31. However, S1P1 activates mTOR in nTreg cells but not naïve T cells immediately after TCR stimulation14. Given the effects of S1P1 on sustained but not early Smad3 activation, we examined mTOR activity at later time points by assessing the phosphorylation of the ribosomal protein S6, a well-established target of mTOR. S1P1-Tg cells exhibited increased amounts of p-S6 after 16 h of TCR stimulation, and more prominent increase was observed at later time points, indicating an important role for S1P1 to sustain mTOR activation (Fig. 7a).


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)

S1P1-mTOR axis is targeted by FTY720 and rapamycin(a) Kinetics of mTOR activation in wild-type and S1P1-Tg cells stimulated for various times. (b) Analysis of Smad3 and S6 activation in wild-type and S1P1-Tg cells treated with FTY720 and rapamycin and activated for 2 days. (c,d) Analysis of Foxp3 (c) and IFN-γ expression (d) in OT-II;Rag1−/− and S1P1-Tg;OT-II;Rag1−/− mice fed with Ova in the drinking water for 5 days, accompanied by daily FTY720 (1 mg/kg) or rapamycin (3 mg/kg) treatment. (e) Analysis of Foxp3 expression in thymic CD4SP cells from wild-type and S1P1-Tg mice treated daily with FTY720 and rapamycin for a total of 5 days. Data represent three independent experiments. (f) Induction of Foxp3 in thymic Treg precursors from wild-type and S1pr1flox/flox;Cd4-Cre mice stimulated with IL-2 (50 U/ml) in the presence of SIS3.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2958252&req=5

Figure 7: S1P1-mTOR axis is targeted by FTY720 and rapamycin(a) Kinetics of mTOR activation in wild-type and S1P1-Tg cells stimulated for various times. (b) Analysis of Smad3 and S6 activation in wild-type and S1P1-Tg cells treated with FTY720 and rapamycin and activated for 2 days. (c,d) Analysis of Foxp3 (c) and IFN-γ expression (d) in OT-II;Rag1−/− and S1P1-Tg;OT-II;Rag1−/− mice fed with Ova in the drinking water for 5 days, accompanied by daily FTY720 (1 mg/kg) or rapamycin (3 mg/kg) treatment. (e) Analysis of Foxp3 expression in thymic CD4SP cells from wild-type and S1P1-Tg mice treated daily with FTY720 and rapamycin for a total of 5 days. Data represent three independent experiments. (f) Induction of Foxp3 in thymic Treg precursors from wild-type and S1pr1flox/flox;Cd4-Cre mice stimulated with IL-2 (50 U/ml) in the presence of SIS3.
Mentions: We further explored the signaling pathway utilized by S1P1 to antagonize TGF-β-Smad3 signaling. The Akt-mTOR pathway has recently been shown to restrain iTreg generation28–31. However, S1P1 activates mTOR in nTreg cells but not naïve T cells immediately after TCR stimulation14. Given the effects of S1P1 on sustained but not early Smad3 activation, we examined mTOR activity at later time points by assessing the phosphorylation of the ribosomal protein S6, a well-established target of mTOR. S1P1-Tg cells exhibited increased amounts of p-S6 after 16 h of TCR stimulation, and more prominent increase was observed at later time points, indicating an important role for S1P1 to sustain mTOR activation (Fig. 7a).

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