{Reference Type}: Journal Article
{Title}: NBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells.
{Author}: Delage L;Carbone F;Riller Q;Zachayus JL;Kerbellec E;Buzy A;Stolzenberg MC;Luka M;de Cevins C;Kalouche G;Favier R;Michel A;Meynier S;Corneau A;Evrard C;Neveux N;Roudières S;Pérot BP;Fusaro M;Lenoir C;Pellé O;Parisot M;Bras M;Héritier S;Leverger G;Korganow AS;Picard C;Latour S;Collet B;Fischer A;Neven B;Magérus A;Ménager M;Pasquier B;Rieux-Laucat F;
{Journal}: Nat Commun
{Volume}: 14
{Issue}: 1
{Year}: 2023 Jun 22
{Factor}: 17.694
{DOI}: 10.1038/s41467-023-39295-7
{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.