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

Rémy Rodriguez; Benjamin Fournier; Debora Jorge Cordeiro; Sarah Winter; Kazushi Izawa; Emmanuel Martin; David Boutboul; Christelle Lenoir; Sylvie Fraitag; Sven Kracker; Tania H Watts; Capucine Picard; Julie Bruneau; Isabelle Callebaut; Alain Fischer; Bénédicte Neven; Sylvain Latour

doi:10.1084/jem.20190678

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

J Exp Med. 2019 Dec 2;216(12):2800-2818. doi: 10.1084/jem.20190678. Epub 2019 Sep 19.

Authors

Rémy Rodriguez^#^{1

2}, Benjamin Fournier^#^{1

2}, Debora Jorge Cordeiro^#^{1

2}, Sarah Winter^#^{1

2}, Kazushi Izawa¹, Emmanuel Martin¹, David Boutboul^{1

2}, Christelle Lenoir¹, Sylvie Fraitag³, Sven Kracker^{2

4}, Tania H Watts⁵, Capucine Picard^{1

2

6

7}, Julie Bruneau^{2

3}, Isabelle Callebaut⁸, Alain Fischer^{2

7

9

10}, Bénédicte Neven^{2

7}, Sylvain Latour^{11

2}

Affiliations

¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche 1163, Paris, France.
² University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, France.
³ Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁴ Laboratory of Human Lymphohematopoiesis, Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche 1163, Paris, France.
⁵ Department of Immunology, University of Toronto, Toronto, Canada.
⁶ Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁷ Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
⁸ Sorbonne Université, Muséum National d'Histoire Naturelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, Paris, France.
⁹ Collège de France, Paris, France.
¹⁰ Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche 1163, Paris, France.
¹¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche 1163, Paris, France [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Class I Phosphatidylinositol 3-Kinases / chemistry
Class I Phosphatidylinositol 3-Kinases / deficiency*
Disease Susceptibility
Epstein-Barr Virus Infections / diagnosis
Epstein-Barr Virus Infections / etiology*
Germ-Line Mutation
Herpesvirus 4, Human / immunology*
Histocytochemistry
Homozygote
Humans
Immunophenotyping
Loss of Function Mutation
Lymphocyte Activation
Lymphoproliferative Disorders / diagnosis
Lymphoproliferative Disorders / etiology
Lymphoproliferative Disorders / metabolism
Models, Molecular
Pedigree
Phospholipase C gamma / metabolism
Protein Conformation
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases / metabolism
Sequence Analysis, DNA
Signal Transduction
Structure-Activity Relationship
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism*
T-Lymphocytes / virology
Tumor Necrosis Factor Receptor Superfamily, Member 9 / chemistry
Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency*
Virus Activation / genetics*
Virus Activation / immunology*

Substances

TNFRSF9 protein, human
Tumor Necrosis Factor Receptor Superfamily, Member 9
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases
PLCG1 protein, human
Phospholipase C gamma

Associated data

PDB/5T8F
PDB/2RD0
SWISSPROT/O00329
SWISSPROT/P42338
SWISSPROT/P48736
SWISSPROT/P42336