IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses
In: Nature Communications, Jg. 11 (2020), Heft 1, S. 1-16
Online
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Zugriff:
T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.
T cell receptors (TCR) are internalized when activated by their ligands. Here the authors show that the internalized TCRs are localized to endosomes expressing IRAP and Syntaxin 6 to maintain intracellular signalling capacity, whose importance is shown by the absence of efficient polyclonal anti-tumour response in mice with T-specific conditional deletion of IRAP.
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IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses
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Autor/in / Beteiligte Person: | Guermonprez, Pierre ; Peter van Endert ; Andrés Ernesto Zucchetti ; Benadda, Samira ; Evnouchidou, Irini ; Koumantou, Despoina ; Lotersztajn, Sophie ; Hivroz, Claire ; Chappert, Pascal ; Bens, Marcelle ; Weimershaus, Mirjana ; Gross, David A. ; Caillens, Vivien ; Davoust, Jean ; Saveanu, Loredana ; Lab Excellence Inflamex (CRI INSERM U1149 - Bichat Medical Faculty) ; Université Paris Diderot - Paris 7 (UPD7) ; Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) ; Inovarion [Paris] ; Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)) ; Immunité et cancer (U932) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris] ; Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP) ; Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; King‘s College London ; Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE) ; Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon ; Agence Nationale de la Recherche, ANR: IDEX EMERGENCE ANR-18-IDEX-0001 Fondation pour la Recherche Médicale, FRM ; We thank the Agence Nationale pour la Recherche (ANR grants Cytoendostor, ECLIPSE and Help2Kill, IDEX EMERGENCE ANR-18-IDEX-0001) and the Fondation pour la Recherche Medicale (FRM) for financial support. We also thank A. Weiss, A. Alcover, J. Rossy, L. Chamberlain and M. Schindler for recombinant plasmids, S. Chai for providing the IRAPloxlox mice, F. Faure for providing Daju-A2 melanoma cells and Meriem Garfa-Traore for help with FLIM-FRET analysis. We finally thank Gregory Gautier and Olivier Pellé for help with cell sorting experiments. ; ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) ; Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Agence Nationale de la Recherche, ANR: IDEX EMERGENCE ANR-18-IDEX-0001 Fondation pour la Recherche Médicale, FRM. |
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Zeitschrift: | Nature Communications, Jg. 11 (2020), Heft 1, S. 1-16 |
Veröffentlichung: | Nature Portfolio, 2020 |
Medientyp: | unknown |
ISSN: | 2041-1723 (print) |
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