Nature Communications (Jun 2023)
NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
- Laure Delage,
- Francesco Carbone,
- Quentin Riller,
- Jean-Luc Zachayus,
- Erwan Kerbellec,
- Armelle Buzy,
- Marie-Claude Stolzenberg,
- Marine Luka,
- Camille de Cevins,
- Georges Kalouche,
- Rémi Favier,
- Alizée Michel,
- Sonia Meynier,
- Aurélien Corneau,
- Caroline Evrard,
- Nathalie Neveux,
- Sébastien Roudières,
- Brieuc P. Pérot,
- Mathieu Fusaro,
- Christelle Lenoir,
- Olivier Pellé,
- Mélanie Parisot,
- Marc Bras,
- Sébastien Héritier,
- Guy Leverger,
- Anne-Sophie Korganow,
- Capucine Picard,
- Sylvain Latour,
- Bénédicte Collet,
- Alain Fischer,
- Bénédicte Neven,
- Aude Magérus,
- Mickaël Ménager,
- Benoit Pasquier,
- Frédéric Rieux-Laucat
Affiliations
- Laure Delage
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Francesco Carbone
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
- Quentin Riller
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Jean-Luc Zachayus
- Immunology and Inflammation Therapeutic Area, Sanofi
- Erwan Kerbellec
- Checkpoint Immunology, Immunology and Inflammation Therapeutic Area, Sanofi
- Armelle Buzy
- BioStructure and Biophysics, Integrated Drug Discovery, Sanofi
- Marie-Claude Stolzenberg
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Marine Luka
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
- Camille de Cevins
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
- Georges Kalouche
- Cellomics, Translational Sciences, Sanofi
- Rémi Favier
- Assistance Publique-Hôpitaux de Paris, French national reference center for platelet disorders, Armand Trousseau Children Hospital
- Alizée Michel
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Sonia Meynier
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Aurélien Corneau
- Sorbonne Université, UMS037, PASS, Plateforme de cytométrie de la Pitié-Salpêtrière CyPS
- Caroline Evrard
- Immunology and Inflammation Therapeutic Area, Sanofi
- Nathalie Neveux
- Laboratory of Biological Nutrition, EA 4466, Faculty of Pharmacy, Paris University
- Sébastien Roudières
- BioStructure and Biophysics, Integrated Drug Discovery, Sanofi
- Brieuc P. Pérot
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
- Mathieu Fusaro
- Université Paris Cité, Institut Imagine, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection
- Christelle Lenoir
- Université Paris Cité, Institut Imagine, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection
- Olivier Pellé
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Mélanie Parisot
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Université Paris Cité
- Marc Bras
- Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université Paris Cité, Imagine Institute
- Sébastien Héritier
- Sorbonne Université, INSERM UMRS_938, CRSA, AP-HP, Pediatric Oncology Hematology Unit, Hôpital Armand Trousseau
- Guy Leverger
- Sorbonne Université, INSERM UMRS_938, CRSA, AP-HP, Pediatric Oncology Hematology Unit, Hôpital Armand Trousseau
- Anne-Sophie Korganow
- Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital
- Capucine Picard
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants Malades University Hospital, AP-HP
- Sylvain Latour
- Université Paris Cité, Institut Imagine, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection
- Bénédicte Collet
- Pediatric Unit, Centre Hospitalier de Roubaix
- Alain Fischer
- Imagine Institute, INSERM UMR1163, Université Paris Cité
- Bénédicte Neven
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Aude Magérus
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- Mickaël Ménager
- Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
- Benoit Pasquier
- Checkpoint Immunology, Immunology and Inflammation Therapeutic Area, Sanofi
- Frédéric Rieux-Laucat
- Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
- DOI
- https://doi.org/10.1038/s41467-023-39295-7
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 12
Abstract
Abstract Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking-down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in the T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4-immunoglobulin therapy in patients with GPS and autoimmune disease.
