title: Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Luise
authors.initials: L
authors.lastname: Westernberg
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Claire
authors.initials: C
authors.lastname: Conche
authors.affiliation: Department of Pathology, Geisel School of Medicine, Lebanon, United States.|Departments of Microbiology and Immunology, Geisel School of Medicine, Lebanon, United States.
authors.forename: Yina Hsing
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rigaud
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Sabine
authors.initials: S
authors.lastname: Siegemund
authors.affiliation: Department 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 States.
authors.forename: Sayak
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States.
authors.forename: Lyn'Al
authors.initials: L
authors.lastname: Nosaka
authors.affiliation: Department 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 States.
authors.forename: Jayajit
authors.initials: J
authors.lastname: Das
authors.affiliation: Department 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 States.
authors.forename: Karsten
authors.initials: K
authors.lastname: Sauer
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D008810:Mice, Inbred C57BL; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D060168:Thymocytes / Q000502:physiology*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase
keywords: Itpkb; Notch; PI3K; beta-selection; cell biology; immunology; mouse; pre-TCR; thymocytes