Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 12, Pages 2800-2818Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20190678
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Funding
- Ministere de la Recherche (France)
- Ligue Contre le Cancer (France)
- Agence Nationale de la Recherche (France)
- Imagine Institut PhD program - Fondation Bettencourt Schueller
- Fondation pour la Recherche Medicale [FDM20170638301]
- Ligue Contre le Cancer Equipe Labelis'ee (France)
- Institut National de la Sante et de la Recherche Medicale (France)
- Rare Diseases Fondation (France)
- Agence Nationale de la Recherche [ANR-14-CE14-0028-01, ANR-18-CE15-0025-01, ANR-10-IAHU-01]
- European Research Council [ERC-2009-AdG_20090506, FP7-249816]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0028, ANR-18-CE15-0025] Funding Source: Agence Nationale de la Recherche (ANR)
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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 p1106 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 PLC gamma l 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.
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