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NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells

Author

Listed:
  • Laure Delage

    (Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
    Checkpoint Immunology, Immunology and Inflammation Therapeutic Area, Sanofi)

  • Francesco Carbone

    (Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
    Labtech Single-Cell@Imagine, Imagine Institute)

  • 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
    Labtech Single-Cell@Imagine, Imagine Institute)

  • Camille Cevins

    (Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team
    Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D)

  • Georges Kalouche

    (Cellomics, Translational Sciences, Sanofi)

  • Rémi Favier

    (Assistance Publique-Hôpitaux de Paris, French national reference center for platelet disorders, Armand Trousseau Children Hospital
    INSERM Unité Mixte de Recherche 1287, Gustave Roussy Cancer Campus, Paris-Saclay University)

  • 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
    Clinical Chemistry Department, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), 4 Avenue de l’Observatoire)

  • 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
    Flow Cytometry Core Facility, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633)

  • 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
    Study Center for Primary Immunodeficiencies (CEDI), Necker-Enfants Malades University Hospital, AP-HP
    Imagine Institute, INSERM UMR1163, Université Paris Cité)

  • 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
    Department of Paediatric Immuno-Haematology and Rheumatology, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris (AP-HP)
    Collège de France)

  • Bénédicte Neven

    (Université Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases
    Pediatric Immunohematology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP))

  • 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
    Labtech Single-Cell@Imagine, Imagine Institute)

  • 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)

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.

Suggested Citation

  • Laure Delage & Francesco Carbone & Quentin Riller & Jean-Luc Zachayus & Erwan Kerbellec & Armelle Buzy & Marie-Claude Stolzenberg & Marine Luka & Camille Cevins & Georges Kalouche & Rémi Favier & Aliz, 2023. "NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39295-7
    DOI: 10.1038/s41467-023-39295-7
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