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NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated T cells
DELAGE L. 1,2, CARBONE F. 3,4, RILLER Q. 1, ZACHAYUS J. 5, KERBELLEC E. 2, BUZY A. 6, STOLZENBERG M. 1, LUKA M. 3,4, DE CEVINS C. 3,7, FAVIER R. 9,10, EVRARD C. 5, FUSARO M. 14, PICARD C. 13,14,15, LATOUR S. 14, FISCHER A. 15, NEVEN B. 1, MAGÉRUS A. 1, MÉNAGER M. 3,4, PASQUIER B. 2, RIEUX-LAUCAT F. 1
1 Université Paris Cité, Institut Imagine, Laboratoire d’immunogénétique des maladies auto-immunes pédiatriques, INSERM UMR 1163; F-75015 Paris, France., Paris, France; 2 Checkpoint Immunology, Immunology and Inflammation Therapeutic Area, Sanofi; F-94400 Vitry-sur-Seine, France., Vitry-Sur-Seine, France; 3 Université Paris Cité, Institut Imagine, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163; F-75015 Paris, France., Paris, France; 4 Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163; F-75015 Paris, France., Paris, France; 5 Immunology and Inflammation Therapeutic Area, Sanofi; F-94400 Vitry-sur-Seine, France., Vitry-Sur-Seine, France; 6 BioStructure and Biophysics, Integrated Drug Discovery, Sanofi; F- 94400 Vitry-sur-Seine, France., Vitry-Sur-Seine, France; 7 Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D; F- 91380 Chilly-Mazarin, France., Chilly-Mazarin, France; 8 Assistance Publique-Hôpitaux de Paris, French national reference center for platelet disorders, Armand Trousseau Children Hospital ; F-75012 Paris, France, Paris, France; 9 INSERM Unité Mixte de Recherche 1287, Gustave Roussy Cancer Campus, Paris-Saclay University ; F-94805 Villejuif, France., Villejuif, France; 10 Université Paris Cité, Institut Imagine, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163; F-75015 Paris, France., Paris, France; 11 French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker-Enfants Malades University Hospital, AP-HP; F-75015 Paris, France, Paris, France; 12 Study Center for Primary Immunodeficiencies (CEDI), Necker-Enfants Malades University Hospital, AP-HP; F-75015 Paris, France., Paris, France; 13 Imagine Institute, INSERM UMR1163, Université Paris Cité ; F-75015 Paris, France, Paris, France; 14 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); F-75015 Paris, France., Paris, France; 15 Collège de France ; F-75231 Paris, France., Paris, France; 16 Pediatric Immunohematology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP) ; F-75015 Paris, France., Paris, France
Loss of NBEAL2 function leads to gray platelet syndrome (GPS), a bleeding disorder characterized by macrothrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism. 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. LRBA recessive mutations 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.