The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells

Liu, Guangwei; Yang, Kai; Burns, Samir; Shrestha, Sharad; Chi, Hongbo

doi:10.1038/ni.1939

Cited by 286 publications

(286 citation statements)

References 49 publications

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“…Recent reports have demonstrated that S1P 1 suppresses generation of Tregs (15,16), and because KLF2 promotes S1P 1 expression in the CD4 + T-cell lineage (12)(13)(14), we decided to examine the relationship between KLF2 and S1P 1 relative to Treg development. Using Vav-cre transgenic mice to thoroughly excise floxed alleles within the T-cell compartment, including early stages of thymocyte development, we found that S1P 1 gene-targeted mice (Vav-cre; S1P 1 fl/fl or Vav-cre; S1P 1 fl/fl ; Klf2 fl/fl ) expressed increased frequencies of Tregs, whereas this phenotype was not present in animals lacking KLF2 alone (Vav-cre; Klf2 fl/fl ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…KLF2 maintains T-cell homeostasis, in part by promoting expression of sphingosine-1-phosphate receptor 1 (S1P 1 ) (12)(13)(14). Surprisingly, S1P 1 suppresses expression of FoxP3, as evidenced by increased numbers of thymus-derived Treg (tTregs) and induced Treg (iTreg) cells after T cell-specific excision in S1P 1 gene-targeted animals (15,16). On the one hand, studies using Foxo1/3-deficient mice suggest that KLF2 promotes Treg development and/or function, whereas reports using S1P 1 -deficient animals predict an opposing outcome.…”

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confidence: 99%

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KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T cells (Tregs) are a specialized subset of CD4 + T cells that maintain self-tolerance by functionally suppressing autoreactive lymphocytes. The Treg compartment is composed of thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs) that are generated in secondary lymphoid organs after exposure to antigen and specific cytokines, such as TGF-β. With regard to this latter lineage, pTregs [and their ex vivo generated counterparts, induced Tregs (iTregs)] offer particular therapeutic potential because these cells can be raised against specific antigens to limit autoimmunity. We now report that transcription factor Krüppel-like factor 2 (KLF2) is necessary for the generation of iTregs but not tTregs. Moreover, drugs that limit KLF2 proteolysis during T-cell activation enhance iTreg development. To the authors' knowledge, this study identifies the first transcription factor to distinguish between i/pTreg and tTreg ontogeny and demonstrates that KLF2 is a therapeutic target for the production of regulatory T cells.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

Kumar

Rabacal

Maseda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, mTOR plays an essential role in integrating environmental cues. Several previous studies have shown that mTOR critically regulates the differentiation of T cells (37)(38)(39)(40). mTOR in T cells acts to integrate signal 1 (antigen recognition through T-cell receptor) and signal 2, the integrated sum of environmental cues, including CD28, IL-2R, amino acids.…”

Section: Discussionmentioning

confidence: 99%

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

Chang

Burkett

Borges

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-1R to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in T cells. How MyD88 regulates helper T-cell differentiation remains largely unknown, however. Here we demonstrate that MyD88 is an important regulator of IL-17-producing CD4 + T helper cells (Th17) cell proliferation. MyD88-deficient CD4 + T cells showed a defect in Th17 cell differentiation, but not in Th1 cell or Th2 cell differentiation. The impaired IL-17 production from MyD88-deficient CD4 + T cells is not a result of defective RAR-related orphan receptor γt (RORγt) expression. Instead, MyD88 is essential for sustaining the mammalian target of rapamycin (mTOR) activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4 + T cells showed impaired mTOR activation and, consequently, reduced Th17 cell proliferation. Importantly, the absence of MyD88 in T cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Th17 cells by delivering IL-1 signaling during the early differentiation stage and integrating IL-23 signaling to the mTOR complex to expand committed Th17 cells.

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“…Although Th17 cells have not been implicated yet in malaria, FTY720 has been shown to attenuate Th17 cell accumulation in a model of neuritis (53) and in multiple sclerosis patients (54). FTY720 also has been shown to affect regulatory T cells (Tregs) by increasing the expression of IL-10 and CTLA-4 in vitro (55), promoting Treg activity in vivo (56) and more recently by modulating the reciprocal differentiation of inducible Tregs and Th1 cells (57). The role of Tregs in malaria infection remains controversial (58), and therefore the impact of S1P on this cell type during infection requires further investigation.…”

Section: Genetic Approaches Using Hs1plmentioning

confidence: 99%

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney

Hawkes

Kain

et al. 2011

Mol Med

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Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL) -/-mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4 + and CD8 + T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

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The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells

Cited by 286 publications

References 49 publications

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

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