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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1374621

Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development

Provisionally accepted
Christina JF Courreges Christina JF Courreges 1Elizabeth CM Davenport Elizabeth CM Davenport 2Benoit Bilanges Benoit Bilanges 3Elena Rebollo-Gomez Elena Rebollo-Gomez 3Jens Hukelmann Jens Hukelmann 4Priya Schoenfelder Priya Schoenfelder 2James R Edgar James R Edgar 1David Sansom David Sansom 3Cheryl Scudamore Cheryl Scudamore 5Rahul Roychoudhuri Rahul Roychoudhuri 1Oliver A Garden Oliver A Garden 5Bart Vanhaesebroeck Bart Vanhaesebroeck 3Klaus Okkenhaug Klaus Okkenhaug 1*
  • 1 University of Cambridge, Cambridge, England, United Kingdom
  • 2 Babraham Institute (BBSRC), Cambridge, United Kingdom
  • 3 University College London, London, England, United Kingdom
  • 4 Dundee College, Dundee, United Kingdom
  • 5 Royal Veterinary College (RVC), London, United Kingdom

The final, formatted version of the article will be published soon.

    Regulatory T (Treg) cells are essential for the maintenance of immunological tolerance, yet the molecular components required for their maintenance and effector functions remain incompletely defined. Inactivation of VPS34 in Treg cells led to an early, lethal phenotype, with massive effector T cell activation and inflammation, like mice lacking Treg cells completely. However, VPS34-deficient Treg cells developed normally, populated the peripheral lymphoid organs and effectively supressed conventional T cells in vitro.Our data suggest that VPS34 is required for the maintaining normal numbers of mature Treg. Functionally, we observed that lack of VPS34 activity impairs cargo processing upon transendocytosis, that defective autophagy may contribute to, but is not sufficient to explain this lethal phenotype, and that loss of VPS34 activity induces a state of heightened metabolic activity that may interfere with metabolic networks required for maintenance or suppressive functions of Treg cells.

    Keywords: PI3K, Treg, VPS34, Autophagy, Endocytosis

    Received: 22 Jan 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Courreges, Davenport, Bilanges, Rebollo-Gomez, Hukelmann, Schoenfelder, Edgar, Sansom, Scudamore, Roychoudhuri, Garden, Vanhaesebroeck and Okkenhaug. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Klaus Okkenhaug, University of Cambridge, Cambridge, CB2 1TN, England, United Kingdom

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.