Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator found in high levels in the blood. Signaling by S1P through its G protein-coupled receptor S1P1 is critical for the emigration of T cells from lymphoid organs into circulation. FTY720, a drug that targets the S1P/S1P1 pathway, induces immune suppression in transplantation and autoimmune diseases. In the peripheral lymphoid system, S1P1 is expressed on naive T cells but lost upon T cell activation. To determine the significance of S1P1 downregulation and function of S1P1 in peripheral T cells, we developed transgenic mice (S1P1-Tg) that constitutively express S1P1 in T cells. S1P1-Tg mice had impaired clearance of Leishmania major infection and defective contact hypersensitivity reaction, which were associated with reduced numbers of antigen-activated T cells in the draining LN. These results demonstrate that S1P1 signaling regulates systemic trafficking of peripheral T cells and primary immune responses, and highlight that control of levels of S1P1 expression represents an important mechanism of immune regulation. Interestingly, S1P1-Tg mice developed a late-onset systemic autoimmune disease. Accordingly, T cells from S1P1-Tg mice were hyper-responsive to TCR stimulation and resistant to tolerance induction. From these findings, we formulate our central hypothesis that S1P1 mediated cellular and molecular pathways in T cells are critical regulators of systemic autoimmunity and lupus pathogenesis. We further hypothesize that S1P1 signaling abrogates peripheral tolerance mechanisms by affecting cellular pathways in T cells that contribute to systemic autoimmunity, and that S1P1 regulates intrinsic T cell functions through signaling pathways and transcriptional mechanisms. To test these hypotheses, we will:
Specific Aim 1 : Establish the functional significance of S1P1 signaling in peripheral tolerance escape and the pathogenesis of murine lupus in vivo.
Specific Aim 2 : Identify cellular mechanisms mediated by S1P1 signaling in autoimmune regulation.
Specific Aim 3 : Identify S1P1-mediated downstream signaling pathways and gene targets. The long-term goals of our studies are to elucidate pathways regulated by S1P signaling in the immune system. Our studies promise to provide new insights into mechanisms and therapies of autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR053573-04
Application #
7845616
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2007-05-10
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$136,032
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Zeng, Hu; Yang, Kai; Cloer, Caryn et al. (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499:485-90
Yang, Kai; Chi, Hongbo (2012) mTOR and metabolic pathways in T cell quiescence and functional activation. Semin Immunol 24:421-8
Huang, Gonghua; Wang, Yanyan; Chi, Hongbo (2012) Regulation of TH17 cell differentiation by innate immune signals. Cell Mol Immunol 9:287-95
Huang, Gonghua; Wang, Yanyan; Vogel, Peter et al. (2012) Signaling via the kinase p38? programs dendritic cells to drive TH17 differentiation and autoimmune inflammation. Nat Immunol 13:152-61
Chi, Hongbo (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12:325-38
Wang, Yanyan; Huang, Gonghua; Vogel, Peter et al. (2012) Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function. Proc Natl Acad Sci U S A 109:E343-52
Chi, Hongbo (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol Sci 32:16-24
Yang, Kai; Neale, Geoffrey; Green, Douglas R et al. (2011) The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 12:888-97
Wang, Ruoning; Dillon, Christopher P; Shi, Lewis Zhichang et al. (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871-82
Shi, Lewis Z; Wang, Ruoning; Huang, Gonghua et al. (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367-76

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