Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent

• DOI: 10.7554/elife.10786
• Publication Date: 2016-02-11T18:45:15Z
• Authors: Luise Westernberg; Claire Conche; Yina Hsing Huang; Stephanie Rigaud; Yisong Deng; Sabine Siegemund; Sayak Mukherjee; Lyn'Al Nosaka; Jayajit Das; Karsten Sauer
• Keywords: QH301-705.5; Cell Survival; Science; pre-TCR; beta-selection; PI3K; 03 medical and health sciences; Animals; Biology (General); Receptor, Notch1; Cell Proliferation; Phosphoinositide-3 Kinase Inhibitors; 0303 health sciences; Thymocytes; Q; R; Cell Differentiation; Cell Biology; 3. Good health; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor); thymocytes; Medicine; itpkb; notch

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.