Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent
β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptor...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/10786 |
| _version_ | 1811235833501450240 |
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| author | Luise Westernberg Claire Conche Yina Hsing Huang Stephanie Rigaud Yisong Deng Sabine Siegemund Sayak Mukherjee Lyn'Al Nosaka Jayajit Das Karsten Sauer |
| author_facet | Luise Westernberg Claire Conche Yina Hsing Huang Stephanie Rigaud Yisong Deng Sabine Siegemund Sayak Mukherjee Lyn'Al Nosaka Jayajit Das Karsten Sauer |
| author_sort | Luise Westernberg |
| collection | DOAJ |
| description | β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb). Canonically, PI3K is counteracted by the lipid-phosphatases Pten and Inpp5d/SHIP-1. In contrast, Itpkb dampens pre-TCR induced PI3K/Akt signaling by producing IP4, a soluble antagonist of the Akt-activating PI3K-product PIP3. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose metabolism. Thus, non-canonical PI3K-antagonism by Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement. |
| first_indexed | 2024-04-12T11:58:46Z |
| format | Article |
| id | doaj.art-1ae57ac0454547c3a658659fd48d389b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T11:58:46Z |
| publishDate | 2016-02-01 |
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| series | eLife |
| spelling | doaj.art-1ae57ac0454547c3a658659fd48d389b2022-12-22T03:33:54ZengeLife Sciences Publications LtdeLife2050-084X2016-02-01510.7554/eLife.10786Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependentLuise Westernberg0Claire Conche1Yina Hsing Huang2Stephanie Rigaud3Yisong Deng4Sabine Siegemund5Sayak Mukherjee6Lyn'Al Nosaka7Jayajit Das8Karsten Sauer9Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Pathology, Geisel School of Medicine, Lebanon, United States; Departments of Microbiology and Immunology, Geisel School of Medicine, Lebanon, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Pediatrics, The Ohio State University, Columbus, United States; Department of Physics, The Ohio State University, Columbus, United States; Battelle Center for Mathematical Medicine, The Ohio State University, Columbus, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United StatesDepartment of Pediatrics, The Ohio State University, Columbus, United States; Department of Physics, The Ohio State University, Columbus, United States; Battelle Center for Mathematical Medicine, The Ohio State University, Columbus, United StatesDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United Statesβ-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb). Canonically, PI3K is counteracted by the lipid-phosphatases Pten and Inpp5d/SHIP-1. In contrast, Itpkb dampens pre-TCR induced PI3K/Akt signaling by producing IP4, a soluble antagonist of the Akt-activating PI3K-product PIP3. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose metabolism. Thus, non-canonical PI3K-antagonism by Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement.https://elifesciences.org/articles/10786PI3Kitpkbnotchthymocytesbeta-selectionpre-TCR |
| spellingShingle | Luise Westernberg Claire Conche Yina Hsing Huang Stephanie Rigaud Yisong Deng Sabine Siegemund Sayak Mukherjee Lyn'Al Nosaka Jayajit Das Karsten Sauer Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent eLife PI3K itpkb notch thymocytes beta-selection pre-TCR |
| title | Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent |
| title_full | Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent |
| title_fullStr | Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent |
| title_full_unstemmed | Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent |
| title_short | Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent |
| title_sort | non canonical antagonism of pi3k by the kinase itpkb delays thymocyte β selection and renders it notch dependent |
| topic | PI3K itpkb notch thymocytes beta-selection pre-TCR |
| url | https://elifesciences.org/articles/10786 |
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