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Article Dans Une Revue Nature Communications Année : 2023

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

Jean-Luc Zachayus
  • Fonction : Auteur
Erwan Kerbellec
Armelle Buzy
  • Fonction : Auteur
Georges Kalouche
  • Fonction : Auteur
Rémi Favier
  • Fonction : Auteur
Caroline Evrard
  • Fonction : Auteur
Nathalie Neveux
  • Fonction : Auteur
Sébastien Roudières
  • Fonction : Auteur
Mathieu Fusaro
  • Fonction : Auteur
Sébastien Héritier
  • Fonction : Auteur
Guy Leverger
  • Fonction : Auteur
Anne-Sophie Korganow
  • Fonction : Auteur
Bénédicte Collet
  • Fonction : Auteur
Benoit Pasquier
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04246988 , version 1 (17-10-2023)

Identifiants

Citer

Laure Delage, Francesco Carbone, Quentin Riller, Jean-Luc Zachayus, Erwan Kerbellec, et al.. NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells. Nature Communications, 2023, 14 (1), pp.3728. ⟨10.1038/s41467-023-39295-7⟩. ⟨hal-04246988⟩
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