Non-canonical Antagonism of PI3K by the Kinase Itpkb Delays Thymocyte β-selection and Renders It Notch-dependent

Overview

Journal Elife

Specialty Biology

Date 2016 Feb 17

PMID 26880557

Citations 14

Authors

Luise Westernberg

Claire Conche

Yina Hsing Huang

Stephanie Rigaud

Yisong Deng

Sabine Siegemund

Sayak Mukherjee

LynAl Nosaka

Jayajit Das

Karsten Sauer

Affiliations

Soon will be listed here.

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.

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References

Kelly A, Finlay D, Hinton H, Clarke R, Fiorini E, Radtke F . Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J. 2007; 26(14):3441-50. PMC: 1933393. DOI: 10.1038/sj.emboj.7601761. View

Jia Y, Subramanian K, Erneux C, Pouillon V, Hattori H, Jo H . Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils. Immunity. 2007; 27(3):453-67. PMC: 2084373. DOI: 10.1016/j.immuni.2007.07.016. View

Fayard E, Gill J, Paolino M, Hynx D, Hollander G, Hemmings B . Deletion of PKBalpha/Akt1 affects thymic development. PLoS One. 2007; 2(10):e992. PMC: 1991598. DOI: 10.1371/journal.pone.0000992. View

Lucas J, Felices M, Evans J, Berg L . Subtle defects in pre-TCR signaling in the absence of the Tec kinase Itk. J Immunol. 2007; 179(11):7561-7. DOI: 10.4049/jimmunol.179.11.7561. View

Juntilla M, Koretzky G . Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol Lett. 2008; 116(2):104-10. PMC: 2322870. DOI: 10.1016/j.imlet.2007.12.008. View

Jia Y, Loison F, Hattori H, Li Y, Erneux C, Park S . Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis. Proc Natl Acad Sci U S A. 2008; 105(12):4739-44. PMC: 2290809. DOI: 10.1073/pnas.0800218105. View

Janas M, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M . Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4. J Exp Med. 2009; 207(1):247-61. PMC: 2812547. DOI: 10.1084/jem.20091430. View

Trampont P, Tosello-Trampont A, Shen Y, Duley A, Sutherland A, Bender T . CXCR4 acts as a costimulator during thymic beta-selection. Nat Immunol. 2009; 11(2):162-70. PMC: 2808461. DOI: 10.1038/ni.1830. View

Soliman G, Acosta-Jaquez H, Dunlop E, Ekim B, Maj N, Tee A . mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action. J Biol Chem. 2009; 285(11):7866-79. PMC: 2832937. DOI: 10.1074/jbc.M109.096222. View

10.

Sauer K, Cooke M . Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate. Nat Rev Immunol. 2010; 10(4):257-71. PMC: 2922113. DOI: 10.1038/nri2745. View

11.

Fayard E, Moncayo G, Hemmings B, Hollander G . Phosphatidylinositol 3-kinase signaling in thymocytes: the need for stringent control. Sci Signal. 2010; 3(135):re5. DOI: 10.1126/scisignal.3135re5. View

12.

Pozuelo-Rubio M, Leslie N, Murphy J, Mackintosh C . Mechanism of activation of PKB/Akt by the protein phosphatase inhibitor Calyculin A. Cell Biochem Biophys. 2010; 58(3):147-56. PMC: 3627045. DOI: 10.1007/s12013-010-9101-4. View

13.

Xiong J, Armato M, Yankee T . Immature single-positive CD8+ thymocytes represent the transition from Notch-dependent to Notch-independent T-cell development. Int Immunol. 2010; 23(1):55-64. PMC: 3031305. DOI: 10.1093/intimm/dxq457. View

14.

Yuan J, Tan J, Visan I, Matei I, Urbanellis P, Xu K . Lunatic Fringe prolongs Delta/Notch-induced self-renewal of committed αβ T-cell progenitors. Blood. 2010; 117(4):1184-95. DOI: 10.1182/blood-2010-07-296616. View

15.

Leslie N, Foti M . Non-genomic loss of PTEN function in cancer: not in my genes. Trends Pharmacol Sci. 2011; 32(3):131-40. DOI: 10.1016/j.tips.2010.12.005. View

16.

Moran A, Holzapfel K, Xing Y, Cunningham N, Maltzman J, Punt J . T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med. 2011; 208(6):1279-89. PMC: 3173240. DOI: 10.1084/jem.20110308. View

17.

Tussiwand R, Engdahl C, Gehre N, Bosco N, Ceredig R, Rolink A . The preTCR-dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL-7 signaling. Eur J Immunol. 2011; 41(11):3371-80. DOI: 10.1002/eji.201141824. View

18.

Wang R, Dillon C, Shi L, Milasta S, Carter R, Finkelstein D . The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35(6):871-82. PMC: 3248798. DOI: 10.1016/j.immuni.2011.09.021. View

19.

Lee K, Nam K, Cho S, Gudapati P, Hwang Y, Park D . Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med. 2012; 209(4):713-28. PMC: 3328370. DOI: 10.1084/jem.20111470. View

20.

Pobezinsky L, Angelov G, Tai X, Jeurling S, Van Laethem F, Feigenbaum L . Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol. 2012; 13(6):569-78. PMC: 3362677. DOI: 10.1038/ni.2292. View