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 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 and Frédéric Rieux-Laucat ()
Additional contact information
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 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

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-39295-7

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