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The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR
Open accessAbstract
Regulatory T cells (T(reg) cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T(reg) cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T(reg) cell-mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.
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“Furthermore, the TTC3 gene is also involved in the regulation of AKT signaling and is related with immune tolerance and neuronal cell survival (Chen et al., 2003; Liu et al., 2009; Pulst, 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Liu et al., 2009
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Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
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Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
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Self-citationRegulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
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Regulatory T cells: mechanisms of differentiation and function
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Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803
Self-citationRegulatory T cells exert checks and balances on self tolerance and autoimmunity
Wing, K., & Sakaguchi, S. (2009) · Nature Immunology · doi:10.1038/ni.1818 · Cited by 1,140
Regulation and function of mTOR signalling in T cell fate decisions
Chi, H. (2012) · Nature Reviews Immunology · doi:10.1038/nri3198 · Cited by 1,035
Self-citationInterleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity
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Metadata
- Authors
- Liu, G., Burns, S., Huang, G., Boyd, K., Proia, R. L., Flavell, R. A., & Chi, H.
- Affiliations
- St. Jude Children's Research Hospital (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chi, Hongbo
- Venue
- Nature Immunology
- Published
- 2009-05-31
- Volume
- 10
- Issue
- 7
- Pages
- 769-777
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC2732340
- OpenAlex
- W1989291933
- Cited by
- 339
- References
- 50
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 15 · 2023: 13 · 2022: 15 · 2021: 21 · 2020: 15 · 2019: 18 · 2018: 11 · 2017: 25 · 2016: 23 · 2015: 26 · 2014: 28 · 2013: 22 · 2012: 34
- FWCI
- 13.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS064599)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR053573)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- S1P1 receptor, sphingosine-1-phosphate, regulatory T cells, Akt/mTOR signaling, immune tolerance, immunosuppression, peripheral tolerance, lymphocyte priming, immune homeostasis, lipid signaling
- MeSH terms
- Animals, Animals, Newborn, Carrier Proteins, Cell Differentiation, Colon, Female, Flow Cytometry, Homeostasis, Immune Tolerance, Male, Mice, Inbred C57BL, Mice, Transgenic, Thymus Gland, Signal Transduction, CD4-Positive T-Lymphocytes, Leukocyte Common Antigens, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Adoptive Transfer, Receptors, Lysosphingolipid, T-Lymphocytes, Regulatory, Proto-Oncogene Proteins c-akt, Mice, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, TOR Serine-Threonine Kinases
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