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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The TTC3 gene is involved in the regulation of AKT signaling and is related with immune tolerance and neuronal cell survival.
“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
The Introduction links regulatory T cells to immune tolerance, and the Results section “S1P1 signals through Akt-mTOR to affect Treg cells” links Akt signaling to their suppressive function (page numbers unavailable). The paper attributes that signaling effect to S1P1, not TTC3; it does not address TTC3 or neuronal cell survival. (LLM, conf=0.85)
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- 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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