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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 is required to restrain the generation and maintenance of Foxp3+ iTreg cells(a) Analysis of Foxp3 expression 4 weeks after Foxp3− CD4SP thymocytes from wild-type and S1pr1flox/flox;Cd4-Cre mice were transferred into Rag1−/− mice. PLN, peripheral lymph nodes. (b) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4-OHT and then activated in the presence of TGF-β for iTreg differentiation. The right panels show proportions and absolute numbers of Foxp3+ and Foxp3− T cells. (c) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4- OHT and then activated by CD103+ DCs and anti-CD3, without any exogenous cytokines. (d) Analysis of Foxp3 expression in mature iTreg cells upon acute deletion of S1P1. Naïve T cells from wild-type and S1pr1CreER mice were differentiated into iTreg cells. Foxp3+ (GFP+) cells were sorted, treated with 4-OHT and cultured with IL-2. Foxp3 expression was analyzed 4–5 days later. Data represent three independent experiments.
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Figure 2: S1P1 is required to restrain the generation and maintenance of Foxp3+ iTreg cells(a) Analysis of Foxp3 expression 4 weeks after Foxp3− CD4SP thymocytes from wild-type and S1pr1flox/flox;Cd4-Cre mice were transferred into Rag1−/− mice. PLN, peripheral lymph nodes. (b) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4-OHT and then activated in the presence of TGF-β for iTreg differentiation. The right panels show proportions and absolute numbers of Foxp3+ and Foxp3− T cells. (c) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4- OHT and then activated by CD103+ DCs and anti-CD3, without any exogenous cytokines. (d) Analysis of Foxp3 expression in mature iTreg cells upon acute deletion of S1P1. Naïve T cells from wild-type and S1pr1CreER mice were differentiated into iTreg cells. Foxp3+ (GFP+) cells were sorted, treated with 4-OHT and cultured with IL-2. Foxp3 expression was analyzed 4–5 days later. Data represent three independent experiments.

Mentions: We then tested whether S1P1 is required to suppress iTreg differentiation. Given the marked reduction of peripheral T cells in S1pr1flox/flox mice crossed with Cd4-Cre transgenic mice14, we bred these mice onto the Foxp3gfp background and purified Foxp3− CD4 single-positive (CD4SP) thymocytes. When transferred into Rag1−/− mice, a subset of donor cells became Foxp3+. Deficiency of S1P1 resulted in an augmented Foxp3+ population, indicating increased iTreg generation in vivo (Fig. 2a). To more directly address the requirement of S1P1 in iTreg development from peripheral T cells, we crossed S1pr1flox/flox mice with Rosa26-Cre-ERT2 (called ‘S1pr1CreER mice’ here). After 4-hydroxytamoxifen (4-OHT) treatment, the floxed S1pr1 gene was deleted in naïve T cells (Supplementary Fig. 3a). When these cells were differentiated toward iTreg cells by exogenous TGF-β, they exhibited a higher frequency of the Foxp3+ population (Fig. 2b), associated with increased Foxp3 mRNA abundance (Supplementary Fig. 3b) and normal cell survival (data not shown). Moreover, CD103+ DC-induced Foxp3+ population was also enhanced in the absence of S1P1 (Fig. 2c). Therefore, S1P1 deficiency directly potentiates iTreg differentiation.


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 is required to restrain the generation and maintenance of Foxp3+ iTreg cells(a) Analysis of Foxp3 expression 4 weeks after Foxp3− CD4SP thymocytes from wild-type and S1pr1flox/flox;Cd4-Cre mice were transferred into Rag1−/− mice. PLN, peripheral lymph nodes. (b) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4-OHT and then activated in the presence of TGF-β for iTreg differentiation. The right panels show proportions and absolute numbers of Foxp3+ and Foxp3− T cells. (c) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4- OHT and then activated by CD103+ DCs and anti-CD3, without any exogenous cytokines. (d) Analysis of Foxp3 expression in mature iTreg cells upon acute deletion of S1P1. Naïve T cells from wild-type and S1pr1CreER mice were differentiated into iTreg cells. Foxp3+ (GFP+) cells were sorted, treated with 4-OHT and cultured with IL-2. Foxp3 expression was analyzed 4–5 days later. Data represent three independent experiments.
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Figure 2: S1P1 is required to restrain the generation and maintenance of Foxp3+ iTreg cells(a) Analysis of Foxp3 expression 4 weeks after Foxp3− CD4SP thymocytes from wild-type and S1pr1flox/flox;Cd4-Cre mice were transferred into Rag1−/− mice. PLN, peripheral lymph nodes. (b) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4-OHT and then activated in the presence of TGF-β for iTreg differentiation. The right panels show proportions and absolute numbers of Foxp3+ and Foxp3− T cells. (c) Analysis of Foxp3 expression after naïve T cells from wild-type and S1pr1CreER mice were treated with 4- OHT and then activated by CD103+ DCs and anti-CD3, without any exogenous cytokines. (d) Analysis of Foxp3 expression in mature iTreg cells upon acute deletion of S1P1. Naïve T cells from wild-type and S1pr1CreER mice were differentiated into iTreg cells. Foxp3+ (GFP+) cells were sorted, treated with 4-OHT and cultured with IL-2. Foxp3 expression was analyzed 4–5 days later. Data represent three independent experiments.
Mentions: We then tested whether S1P1 is required to suppress iTreg differentiation. Given the marked reduction of peripheral T cells in S1pr1flox/flox mice crossed with Cd4-Cre transgenic mice14, we bred these mice onto the Foxp3gfp background and purified Foxp3− CD4 single-positive (CD4SP) thymocytes. When transferred into Rag1−/− mice, a subset of donor cells became Foxp3+. Deficiency of S1P1 resulted in an augmented Foxp3+ population, indicating increased iTreg generation in vivo (Fig. 2a). To more directly address the requirement of S1P1 in iTreg development from peripheral T cells, we crossed S1pr1flox/flox mice with Rosa26-Cre-ERT2 (called ‘S1pr1CreER mice’ here). After 4-hydroxytamoxifen (4-OHT) treatment, the floxed S1pr1 gene was deleted in naïve T cells (Supplementary Fig. 3a). When these cells were differentiated toward iTreg cells by exogenous TGF-β, they exhibited a higher frequency of the Foxp3+ population (Fig. 2b), associated with increased Foxp3 mRNA abundance (Supplementary Fig. 3b) and normal cell survival (data not shown). Moreover, CD103+ DC-induced Foxp3+ population was also enhanced in the absence of S1P1 (Fig. 2c). Therefore, S1P1 deficiency directly potentiates iTreg differentiation.

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