Limits...
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.

Show MeSH

Related in: MedlinePlus

S1P1 mediates iTreg and TH1 differentiation through discrete mechanisms(a) Analysis of Foxp3 expression after wild-type and Ifng−/− naïve T cells were transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) and activated in the presence of TGF-β differentiation. (b) Analysis of Foxp3 expression after naïve T cells from Ifng−/− and for iTregS1P1-Tg;Ifng−/− mice were differentiated in the presence of different doses of TGF-β. (c) Analysis of IFN-γ expression in wild-type and S1P1-Tg cells activated under TH0 conditions and transduced with control (RV) and Foxp3-expressing retrovirus (Foxp3-RV) linked with a GFP reporter; gated GFP+ cells are shown in the FACS plots. (d) Analysis of IFN-γ expression in Foxp3-deficient cells. Wild-type (CD45.2+) and Scurfy (CD45.1+.2+) bone marrow cells were mixed at 1:1, and transferred into sublethally irradiated Rag1−/− mice. At 6 weeks after reconstitution, naïve T cells from the two donor populations were purified, activated under TH0 conditions, and transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) linked with a Thy1.1 reporter; gated Thy1.1+ cells are shown in the FACS plots. (e) Analysis of IFN-γ expression in Foxp3-deficient cells after naïve T cells from OT-II and S1P1-Tg;OT-II mice bred onto the Scurfy background were activated by Ova and irradiated splenic APC. Data represent three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2958252&req=5

Figure 5: S1P1 mediates iTreg and TH1 differentiation through discrete mechanisms(a) Analysis of Foxp3 expression after wild-type and Ifng−/− naïve T cells were transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) and activated in the presence of TGF-β differentiation. (b) Analysis of Foxp3 expression after naïve T cells from Ifng−/− and for iTregS1P1-Tg;Ifng−/− mice were differentiated in the presence of different doses of TGF-β. (c) Analysis of IFN-γ expression in wild-type and S1P1-Tg cells activated under TH0 conditions and transduced with control (RV) and Foxp3-expressing retrovirus (Foxp3-RV) linked with a GFP reporter; gated GFP+ cells are shown in the FACS plots. (d) Analysis of IFN-γ expression in Foxp3-deficient cells. Wild-type (CD45.2+) and Scurfy (CD45.1+.2+) bone marrow cells were mixed at 1:1, and transferred into sublethally irradiated Rag1−/− mice. At 6 weeks after reconstitution, naïve T cells from the two donor populations were purified, activated under TH0 conditions, and transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) linked with a Thy1.1 reporter; gated Thy1.1+ cells are shown in the FACS plots. (e) Analysis of IFN-γ expression in Foxp3-deficient cells after naïve T cells from OT-II and S1P1-Tg;OT-II mice bred onto the Scurfy background were activated by Ova and irradiated splenic APC. Data represent three independent experiments.

Mentions: We next determined whether control of TH1 and iTreg differentiation by S1P1 is interdependent. IFN-γ can inhibit iTreg generation20, although conflicting conclusions also exist21. We tested whether inhibition of iTreg differentiation by S1P1 is a secondary consequence of increased IFN-γ production. Retroviral transduction of S1P1 into either Ifng−/− or wild-type cells resulted in diminished Foxp3+ induction under iTreg conditions (Fig. 5a). Also, the S1P1 transgene downregulated iTreg generation in both Ifng+/+ and Ifng−/− backgrounds (Fig. 5b). Thus, S1P1 regulates iTreg differentiation independent of its role in facilitating IFN-γ expression.


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 mediates iTreg and TH1 differentiation through discrete mechanisms(a) Analysis of Foxp3 expression after wild-type and Ifng−/− naïve T cells were transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) and activated in the presence of TGF-β differentiation. (b) Analysis of Foxp3 expression after naïve T cells from Ifng−/− and for iTregS1P1-Tg;Ifng−/− mice were differentiated in the presence of different doses of TGF-β. (c) Analysis of IFN-γ expression in wild-type and S1P1-Tg cells activated under TH0 conditions and transduced with control (RV) and Foxp3-expressing retrovirus (Foxp3-RV) linked with a GFP reporter; gated GFP+ cells are shown in the FACS plots. (d) Analysis of IFN-γ expression in Foxp3-deficient cells. Wild-type (CD45.2+) and Scurfy (CD45.1+.2+) bone marrow cells were mixed at 1:1, and transferred into sublethally irradiated Rag1−/− mice. At 6 weeks after reconstitution, naïve T cells from the two donor populations were purified, activated under TH0 conditions, and transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) linked with a Thy1.1 reporter; gated Thy1.1+ cells are shown in the FACS plots. (e) Analysis of IFN-γ expression in Foxp3-deficient cells after naïve T cells from OT-II and S1P1-Tg;OT-II mice bred onto the Scurfy background were activated by Ova and irradiated splenic APC. Data represent three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: S1P1 mediates iTreg and TH1 differentiation through discrete mechanisms(a) Analysis of Foxp3 expression after wild-type and Ifng−/− naïve T cells were transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) and activated in the presence of TGF-β differentiation. (b) Analysis of Foxp3 expression after naïve T cells from Ifng−/− and for iTregS1P1-Tg;Ifng−/− mice were differentiated in the presence of different doses of TGF-β. (c) Analysis of IFN-γ expression in wild-type and S1P1-Tg cells activated under TH0 conditions and transduced with control (RV) and Foxp3-expressing retrovirus (Foxp3-RV) linked with a GFP reporter; gated GFP+ cells are shown in the FACS plots. (d) Analysis of IFN-γ expression in Foxp3-deficient cells. Wild-type (CD45.2+) and Scurfy (CD45.1+.2+) bone marrow cells were mixed at 1:1, and transferred into sublethally irradiated Rag1−/− mice. At 6 weeks after reconstitution, naïve T cells from the two donor populations were purified, activated under TH0 conditions, and transduced with control (RV) and S1P1-expressing retrovirus (S1P1-RV) linked with a Thy1.1 reporter; gated Thy1.1+ cells are shown in the FACS plots. (e) Analysis of IFN-γ expression in Foxp3-deficient cells after naïve T cells from OT-II and S1P1-Tg;OT-II mice bred onto the Scurfy background were activated by Ova and irradiated splenic APC. Data represent three independent experiments.
Mentions: We next determined whether control of TH1 and iTreg differentiation by S1P1 is interdependent. IFN-γ can inhibit iTreg generation20, although conflicting conclusions also exist21. We tested whether inhibition of iTreg differentiation by S1P1 is a secondary consequence of increased IFN-γ production. Retroviral transduction of S1P1 into either Ifng−/− or wild-type cells resulted in diminished Foxp3+ induction under iTreg conditions (Fig. 5a). Also, the S1P1 transgene downregulated iTreg generation in both Ifng+/+ and Ifng−/− backgrounds (Fig. 5b). Thus, S1P1 regulates iTreg differentiation independent of its role in facilitating IFN-γ expression.

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