Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb
Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell...
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| Vydané v: | Immunity (Cambridge, Mass.) Ročník 51; číslo 6; s. 1012 |
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| Hlavní autori: | , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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17.12.2019
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| ISSN: | 1097-4180, 1097-4180 |
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| Abstract | Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells. |
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| AbstractList | Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells. Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells.Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells. |
| Author | Guy, Cliff Vogel, Peter Long, Lingyun Peng, Junmin Wen, Jing Chi, Hongbo Pelletier, Stephane Chapman, Nicole M Wang, Hong Dhungana, Yogesh Rankin, Sherri Guan, Kun-Liang Shi, Hao |
| Author_xml | – sequence: 1 givenname: Hao surname: Shi fullname: Shi, Hao organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 2 givenname: Nicole M surname: Chapman fullname: Chapman, Nicole M organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 3 givenname: Jing surname: Wen fullname: Wen, Jing organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 4 givenname: Cliff surname: Guy fullname: Guy, Cliff organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 5 givenname: Lingyun surname: Long fullname: Long, Lingyun organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 6 givenname: Yogesh surname: Dhungana fullname: Dhungana, Yogesh organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 7 givenname: Sherri surname: Rankin fullname: Rankin, Sherri organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 8 givenname: Stephane surname: Pelletier fullname: Pelletier, Stephane organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 9 givenname: Peter surname: Vogel fullname: Vogel, Peter organization: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 10 givenname: Hong surname: Wang fullname: Wang, Hong organization: Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 11 givenname: Junmin surname: Peng fullname: Peng, Junmin organization: Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA – sequence: 12 givenname: Kun-Liang surname: Guan fullname: Guan, Kun-Liang organization: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA – sequence: 13 givenname: Hongbo surname: Chi fullname: Chi, Hongbo email: hongbo.chi@stjude.org organization: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: hongbo.chi@stjude.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31668641$$D View this record in MEDLINE/PubMed |
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| Keywords | autoimmunity Rheb eTreg cells amino acids mTOR Treg cells metabolism RagB RagA |
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| SubjectTerms | Animals Arginine - metabolism Cell Cycle Cell Differentiation - physiology Cell Line Humans Immune Tolerance - immunology Leucine - metabolism Lymphocyte Activation - immunology Mechanistic Target of Rapamycin Complex 1 - metabolism Mice Mice, Inbred C57BL Mice, Knockout Monomeric GTP-Binding Proteins - genetics Monomeric GTP-Binding Proteins - metabolism Ras Homolog Enriched in Brain Protein - genetics Ras Homolog Enriched in Brain Protein - metabolism Receptors, Antigen, T-Cell - immunology T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - immunology |
| Title | Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb |
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