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      S1P 1-mTOR axis directs the reciprocal differentiation of T H1 and regulatory T cells

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          Abstract

          Naïve CD4 + T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. The differentiation of pro-inflammatory T H1 and anti-inflammatory Foxp3+ regulatory T cells (Treg) was reciprocally regulated by S1P 1, a receptor for the bioactive lipid sphingosine-1-phosphate. S1P 1 inhibited extrathymic and natural Treg generation while driving T H1 cell development in a reciprocal manner and disrupted immune homeostasis. S1P 1 signaled through mTOR and antagonized TGF-β function mainly by attenuating sustained Smad3 activity. S1P 1 function was dependent upon endogenous sphingosine kinase activity. Remarkably, two seemingly unrelated immunosuppressants FTY720 and rapamycin targeted the same S1P 1 and mTOR pathway to regulate the dichotomy between T H1 and Treg cells. Our studies establish an S1P 1-mTOR axis that controls T cell lineage specification.

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          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Mehrdad Matloubian, Charles G Lo, Guy Cinamon … (2004)
          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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            Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.

            Xuexian O. Yang, Roza Nurieva, Gustavo Martínez … (2008)
            Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.
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              T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.

              Stephan Sauer, Ludovica Bruno, Arnulf Hertweck … (2008)
              Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control the de novo expression of Foxp3 in naive peripheral CD4 T cells and in thymocytes. We report that premature termination of TCR signaling and inibition of phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, protein kinase B (Akt), or mammalian target of rapamycin (mTOR) conferred Foxp3 expression and Treg-like gene expression profiles. Conversely, continued TCR signaling and constitutive PI3K/Akt/mTOR activity antagonised Foxp3 induction. At the chromatin level, di- and trimethylation of lysine 4 of histone H3 (H3K4me2 and -3) near the Foxp3 transcription start site (TSS) and within the 5' untranslated region (UTR) preceded active Foxp3 expression and, like Foxp3 inducibility, was lost upon continued TCR stimulation. These data demonstrate that the PI3K/Akt/mTOR signaling network regulates Foxp3 expression.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 30 August 2010
                Publication date (Electronic): 19 September 2010
                Publication date (Print): November 2010
                Publication date PMC-release: 1 May 2011
                Volume: 11
                Issue: 11
                Pages: 1047-1056
                Affiliations
                [1 ] Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
                Author notes
                Correspondence should be addressed to: Hongbo Chi, Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA. Phone: 901-595-6282; Fax: 901-595-5766; hongbo.chi@ 123456stjude.org
                [2]

                These authors contributed equally to this work.

                Article
                Manuscript ID: nihpa231236
                DOI: 10.1038/ni.1939
                PMC ID: 2958252
                PubMed ID: 20852647
                SO-VID: ec8b2031-a703-4fd5-8df7-9e609b782c89
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R01 NS064599-03 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K01 AR053573-03S1 ||AR
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: K01 AR053573-03 ||AR
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Keywords: t cell differentiation,immunosuppressant,mtor,regulatory t cells
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: t cell differentiation, immunosuppressant, mtor, regulatory t cells

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