Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1374621/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850146935380377600 |
|---|---|
| author | Christina J. F. Courreges Christina J. F. Courreges Elizabeth C. M. Davenport Elizabeth C. M. Davenport Benoit Bilanges Elena Rebollo-Gomez Jens Hukelmann Priya Schoenfelder James R. Edgar David Sansom Cheryl L. Scudamore Rahul Roychoudhuri Oliver A. Garden Bart Vanhaesebroeck Klaus Okkenhaug Klaus Okkenhaug |
| author_facet | Christina J. F. Courreges Christina J. F. Courreges Elizabeth C. M. Davenport Elizabeth C. M. Davenport Benoit Bilanges Elena Rebollo-Gomez Jens Hukelmann Priya Schoenfelder James R. Edgar David Sansom Cheryl L. Scudamore Rahul Roychoudhuri Oliver A. Garden Bart Vanhaesebroeck Klaus Okkenhaug Klaus Okkenhaug |
| author_sort | Christina J. F. Courreges |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-76c0dafb2bb54d09976bae31a2ce382f |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-76c0dafb2bb54d09976bae31a2ce382f2025-08-20T02:27:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-11-011510.3389/fimmu.2024.13746211374621Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their developmentChristina J. F. Courreges0Christina J. F. Courreges1Elizabeth C. M. Davenport2Elizabeth C. M. Davenport3Benoit Bilanges4Elena Rebollo-Gomez5Jens Hukelmann6Priya Schoenfelder7James R. Edgar8David Sansom9Cheryl L. Scudamore10Rahul Roychoudhuri11Oliver A. Garden12Bart Vanhaesebroeck13Klaus Okkenhaug14Klaus Okkenhaug15Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United KingdomDepartment of Pathology, The University of Cambridge, Cambridge, United KingdomLaboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United KingdomRoyal Veterinary College, London, United KingdomUCL Cancer Institute, University College London, London, United KingdomUCL Cancer Institute, University College London, London, United KingdomThe School of Life Sciences, University of Dundee, Dundee, United KingdomLaboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United KingdomDepartment of Pathology, The University of Cambridge, Cambridge, United KingdomInstitute of Immunity and Transplantation, University College London, London, United KingdomRoyal Veterinary College, London, United KingdomDepartment of Pathology, The University of Cambridge, Cambridge, United KingdomRoyal Veterinary College, London, United KingdomUCL Cancer Institute, University College London, London, United KingdomLaboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United KingdomDepartment of Pathology, The University of Cambridge, Cambridge, United KingdomRegulatory 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1374621/fullPI3KTregVPS34autophagyendocytosis |
| spellingShingle | Christina J. F. Courreges Christina J. F. Courreges Elizabeth C. M. Davenport Elizabeth C. M. Davenport Benoit Bilanges Elena Rebollo-Gomez Jens Hukelmann Priya Schoenfelder James R. Edgar David Sansom Cheryl L. Scudamore Rahul Roychoudhuri Oliver A. Garden Bart Vanhaesebroeck Klaus Okkenhaug Klaus Okkenhaug Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development Frontiers in Immunology PI3K Treg VPS34 autophagy endocytosis |
| title | Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development |
| title_full | Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development |
| title_fullStr | Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development |
| title_full_unstemmed | Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development |
| title_short | Lack of phosphatidylinositol 3-kinase VPS34 in regulatory T cells leads to a fatal lymphoproliferative disorder without affecting their development |
| title_sort | lack of phosphatidylinositol 3 kinase vps34 in regulatory t cells leads to a fatal lymphoproliferative disorder without affecting their development |
| topic | PI3K Treg VPS34 autophagy endocytosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1374621/full |
| work_keys_str_mv | AT christinajfcourreges lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT christinajfcourreges lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT elizabethcmdavenport lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT elizabethcmdavenport lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT benoitbilanges lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT elenarebollogomez lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT jenshukelmann lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT priyaschoenfelder lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT jamesredgar lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT davidsansom lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT cheryllscudamore lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT rahulroychoudhuri lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT oliveragarden lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT bartvanhaesebroeck lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT klausokkenhaug lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment AT klausokkenhaug lackofphosphatidylinositol3kinasevps34inregulatorytcellsleadstoafatallymphoproliferativedisorderwithoutaffectingtheirdevelopment |