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.
Highlights
To generate a diverse T cell repertoire reactive against many pathogens, the T cell receptor (TCR) a and b chain genes somatically rearrange in developing thymocytes
To determine if the Akt/mTOR and metabolic hyperactivation of inositol-trisphosphate 3-kinase B (Itpkb)-/- pre-T cell receptor (pre-TCR)+ DN3 cells causes their accelerated development to DP cells, we studied if treatment with inhibitors of Akt (Aktinhibitor VIII), mTOR or glucose-metabolism (2-deoxy-D-glucose, 2DG) could reverse the increased DP cell generation from equal numbers of sorted Itpkb-/- versus Itpkb+/+ DN3 cells on OP9DL1 stroma
We propose that pre-TCR induced IP4/ PIP3 antagonism governs b-selection by restricting phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling and metabolic activation
Summary
To generate a diverse T cell repertoire reactive against many pathogens, the T cell receptor (TCR) a and b chain genes somatically rearrange in developing thymocytes. Thymocytes develop from bone marrow (BM) progenitors through successive CD4-CD8- ’double-negative’ CD44+CD25-c-Kit+ DN1, CD44+CD25+c-Kit+ DN2, HSAhighcKit-CD44-CD25+ DN3 and HSAhighCD44-CD25- DN4 stages (Petrie and Zuniga-Pflucker, 2007; Xiong et al, 2011). B-selection, ligand-independent pre-TCR signaling triggers DN3 cell metabolic activation, proliferation and survival. It triggers allelic exclusion of the second TCRb allele, initiation of TCRa gene-rearrangements and differentiation via CD8+HSAhighTCRblow immature single positive (ISP) precursors into CD4+CD8+ ’double-positive’ (DP) cells (Petrie and Zuniga-Pflucker, 2007; Xiong et al, 2011). It triggers allelic exclusion of the second TCRb allele, initiation of TCRa gene-rearrangements and differentiation via CD8+HSAhighTCRblow immature single positive (ISP) precursors into CD4+CD8+ ’double-positive’ (DP) cells (Petrie and Zuniga-Pflucker, 2007; Xiong et al, 2011). b-selection ensures that only DN3 cells
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
