Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent
Luise Westernberg,
Claire Conche,
Yina Hsing Huang,
Stephanie Rigaud,
Yisong Deng,
Sabine Siegemund,
Sayak Mukherjee,
Lyn'Al Nosaka,
Jayajit Das,
Karsten Sauer
Affiliations
Luise Westernberg
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Claire Conche
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Yina Hsing Huang
Department of Pathology, Geisel School of Medicine, Lebanon, United States; Departments of Microbiology and Immunology, Geisel School of Medicine, Lebanon, United States
Stephanie Rigaud
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Yisong Deng
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Sabine Siegemund
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Sayak Mukherjee
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
Lyn'Al Nosaka
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, United States
Jayajit Das
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
Karsten Sauer
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
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.
