| First Author | Westernberg L | Year | 2016 |
| Journal | Elife | Volume | 5 |
| PubMed ID | 26880557 | Mgi Jnum | J:231012 |
| Mgi Id | MGI:5766667 | Doi | 10.7554/eLife.10786 |
| Citation | Westernberg L, et al. (2016) Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte beta-selection and renders it Notch-dependent. Elife 5:e10786 |
| abstractText | beta-selection is the most pivotal event determining alphabeta 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, beta-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 beta-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. |
