Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Journal of Experimental Medicine Année : 2019

Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells

Rémy Rodriguez
  • Fonction : Auteur
Debora Jorge Cordeiro
  • Fonction : Auteur
Sarah Winter
Kazushi Izawa
  • Fonction : Auteur
Sven Kracker
Tania Watts
  • Fonction : Auteur
Capucine Picard

Résumé

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand-expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137-CD137L pathway, highlighting its critical role in immunity to EBV.

Domaines

Immunologie
Fichier principal
Vignette du fichier
jem_20190678.pdf (4.02 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-02391542 , version 1 (30-08-2021)

Licence

Paternité

Identifiants

Citer

Rémy Rodriguez, Benjamin Fournier, Debora Jorge Cordeiro, Sarah Winter, Kazushi Izawa, et al.. Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells. Journal of Experimental Medicine, 2019, 216 (12), pp.2800-2818. ⟨10.1084/jem.20190678⟩. ⟨hal-02391542⟩
229 Consultations
59 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More