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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 regulates reciprocal TH1 and iTreg differentiation and immune homeostasis in vivo(a,b) Analysis of IFN-γ and Foxp3 expression in wild-type (a) and S1P1-Tg (b) cells differentiated under the specified conditions. (c,d) Ratios of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (c) and 4-OHT treated wild-type and S1pr1CreER cells (d) that were differentiated under TH1 conditions in the presence of TGF-β. (e,f) Analysis of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (e) and 4-OHT treated wild-type and S1pr1CreER cells (f) that were activated by CD103+ DCs and Ova or anti-CD3, without any exogenous cytokines. (g-i) Analysis of T cell-dependent colitis and in vivo differentiation. Wild-type or S1P1-Tg naive T cells were transferred in combination with wild-type Treg cells (CD45.1+) into Rag1−/− mice. (g) Changes in body weight. (h) Representative intestine histology. (i) Proportions of Foxp3+ and IFN-γ+ CD4 T cells derived from naïve T cell donors. Data represent three independent experiments.
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Figure 4: S1P1 regulates reciprocal TH1 and iTreg differentiation and immune homeostasis in vivo(a,b) Analysis of IFN-γ and Foxp3 expression in wild-type (a) and S1P1-Tg (b) cells differentiated under the specified conditions. (c,d) Ratios of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (c) and 4-OHT treated wild-type and S1pr1CreER cells (d) that were differentiated under TH1 conditions in the presence of TGF-β. (e,f) Analysis of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (e) and 4-OHT treated wild-type and S1pr1CreER cells (f) that were activated by CD103+ DCs and Ova or anti-CD3, without any exogenous cytokines. (g-i) Analysis of T cell-dependent colitis and in vivo differentiation. Wild-type or S1P1-Tg naive T cells were transferred in combination with wild-type Treg cells (CD45.1+) into Rag1−/− mice. (g) Changes in body weight. (h) Representative intestine histology. (i) Proportions of Foxp3+ and IFN-γ+ CD4 T cells derived from naïve T cell donors. Data represent three independent experiments.

Mentions: We next determined the mechanisms for the altered iTreg and TH1 differentiation in S1P1-Tg and deficient cells. TGF-β is a pleiotropic cytokine with pronounced effects on cell fate determination of multiple T cell lineages 17, but whether TGF-β directly coordinates development of TH1 and iTreg cells from naïve precursors is not well understood. We therefore differentiated wild-type naïve cells under TH0 and TH1 conditions in the presence of TGF-β and measured Foxp3 and IFN-γ expression simultaneously. As expected, a subset of cells expressed IFN-γ but few Foxp3+ cells were detected under nonpolarizing conditions. Addition of TGF-β induced Foxp3 and terminated IFN-γ expression. Under TH1 conditions, most T cells became IFN-γ positive, yet addition of TGF-β decreased IFN-γ+ population and simultaneously induced Foxp3+ population, resulting in the co-existence of TH1 and iTreg cells (Fig. 4a). The effects of TGF-β to promote Foxp3 over IFN-γ expression were profoundly lost in S1P1-Tg cells (Fig. 4b). In particular, when TGF-β was added to differentiating TH1 cells to foster development of both TH1 and iTreg cells, the ratio of IFN-γ+: Foxp3+ cells was reversed in S1P1-Tg cells (Fig. 4c). This reciprocal change was also observed in antigen-specific S1P1-Tg;OT-II T cells (Fig. 4c). Conversely, deletion of S1P1 resulted in the expansion of iTreg cells at the expense of TH1 cells (Fig. 4d). Therefore, S1P1 mediates reciprocal TH1 and iTreg differentiation in vitro.


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 regulates reciprocal TH1 and iTreg differentiation and immune homeostasis in vivo(a,b) Analysis of IFN-γ and Foxp3 expression in wild-type (a) and S1P1-Tg (b) cells differentiated under the specified conditions. (c,d) Ratios of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (c) and 4-OHT treated wild-type and S1pr1CreER cells (d) that were differentiated under TH1 conditions in the presence of TGF-β. (e,f) Analysis of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (e) and 4-OHT treated wild-type and S1pr1CreER cells (f) that were activated by CD103+ DCs and Ova or anti-CD3, without any exogenous cytokines. (g-i) Analysis of T cell-dependent colitis and in vivo differentiation. Wild-type or S1P1-Tg naive T cells were transferred in combination with wild-type Treg cells (CD45.1+) into Rag1−/− mice. (g) Changes in body weight. (h) Representative intestine histology. (i) Proportions of Foxp3+ and IFN-γ+ CD4 T cells derived from naïve T cell donors. Data represent three independent experiments.
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Related In: Results  -  Collection

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Figure 4: S1P1 regulates reciprocal TH1 and iTreg differentiation and immune homeostasis in vivo(a,b) Analysis of IFN-γ and Foxp3 expression in wild-type (a) and S1P1-Tg (b) cells differentiated under the specified conditions. (c,d) Ratios of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (c) and 4-OHT treated wild-type and S1pr1CreER cells (d) that were differentiated under TH1 conditions in the presence of TGF-β. (e,f) Analysis of IFN-γ+ and Foxp3+ populations in wild-type and S1P1-Tg cells (e) and 4-OHT treated wild-type and S1pr1CreER cells (f) that were activated by CD103+ DCs and Ova or anti-CD3, without any exogenous cytokines. (g-i) Analysis of T cell-dependent colitis and in vivo differentiation. Wild-type or S1P1-Tg naive T cells were transferred in combination with wild-type Treg cells (CD45.1+) into Rag1−/− mice. (g) Changes in body weight. (h) Representative intestine histology. (i) Proportions of Foxp3+ and IFN-γ+ CD4 T cells derived from naïve T cell donors. Data represent three independent experiments.
Mentions: We next determined the mechanisms for the altered iTreg and TH1 differentiation in S1P1-Tg and deficient cells. TGF-β is a pleiotropic cytokine with pronounced effects on cell fate determination of multiple T cell lineages 17, but whether TGF-β directly coordinates development of TH1 and iTreg cells from naïve precursors is not well understood. We therefore differentiated wild-type naïve cells under TH0 and TH1 conditions in the presence of TGF-β and measured Foxp3 and IFN-γ expression simultaneously. As expected, a subset of cells expressed IFN-γ but few Foxp3+ cells were detected under nonpolarizing conditions. Addition of TGF-β induced Foxp3 and terminated IFN-γ expression. Under TH1 conditions, most T cells became IFN-γ positive, yet addition of TGF-β decreased IFN-γ+ population and simultaneously induced Foxp3+ population, resulting in the co-existence of TH1 and iTreg cells (Fig. 4a). The effects of TGF-β to promote Foxp3 over IFN-γ expression were profoundly lost in S1P1-Tg cells (Fig. 4b). In particular, when TGF-β was added to differentiating TH1 cells to foster development of both TH1 and iTreg cells, the ratio of IFN-γ+: Foxp3+ cells was reversed in S1P1-Tg cells (Fig. 4c). This reciprocal change was also observed in antigen-specific S1P1-Tg;OT-II T cells (Fig. 4c). Conversely, deletion of S1P1 resulted in the expansion of iTreg cells at the expense of TH1 cells (Fig. 4d). Therefore, S1P1 mediates reciprocal TH1 and iTreg differentiation in vitro.

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