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

Elife. 2016 Feb 11:5:e10786. doi: 10.7554/eLife.10786.

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.

Keywords: Itpkb; Notch; PI3K; beta-selection; cell biology; immunology; mouse; pre-TCR; thymocytes.

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Proliferation*
  • Cell Survival
  • Mice, Inbred C57BL
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Receptor, Notch1 / metabolism*
  • Thymocytes / physiology*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Receptor, Notch1
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase