2. Academic Validation
  3. Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency

  • Nature. 2024 Apr;628(8008):620-629. doi: 10.1038/s41586-024-07213-6.
Emmanuel Martin 1,  Sarah Winter 1 2,  Cécile Garcin # 1 2,  Kay Tanita # 1,  Akihiro Hoshino # 1,  Christelle Lenoir # 1,  Benjamin Fournier 1 3,  Mélanie Migaud 4,  David Boutboul 2 5,  Mathieu Simonin 1,  Alicia Fernandes 6,  Paul Bastard 2 4,  Tom Le Voyer 2 4,  Anne-Laure Roupie 1 2,  Yassine Ben Ahmed 1,  Marianne Leruez-Ville 7,  Marianne Burgard 7,  Geetha Rao 8,  Cindy S Ma 8 9,  Cécile Masson 10,  Claire Soudais 1 2,  Capucine Picard 1 2 11,  Jacinta Bustamante 2 4 11 12,  Stuart G Tangye 8 9,  Nathalie Cheikh 13,  Mikko Seppänen 14,  Anne Puel 2 4 12,  Mark Daly 15,  Jean-Laurent Casanova 2 3 4 12 16,  Bénédicte Neven 3,  Alain Fischer 3 17 18,  Sylvain Latour 19 20
Affiliations

Affiliations

  • 1 Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.
  • 2 Université Paris Cité, Paris, France.
  • 3 Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 4 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France.
  • 5 Department of Hematology, Cochin Hospital, AP-HP, Paris, France.
  • 6 Plateforme Vecteurs Viraux et Transfert de Gènes, Institut Necker Enfants Malades, Necker-Enfants Malades Hospital, APHP, Paris, France.
  • 7 Service de Bactériologie, Virologie, Parasitologie et Hygiène, Necker-Enfants Malades Hospital, Paris, France.
  • 8 Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
  • 9 St Vincent's Clinical School, Faculty of Medicine and Health, Sydney, New South Wales, Australia.
  • 10 Plateforme de Bioinformatique, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
  • 11 Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, APHP, Paris, France.
  • 12 St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 13 Hôpital Jean Minjoz, Centre Hospitalo-Universitaire de Besançon, Besançon, France.
  • 14 Pediatric Research Center and Rare Disease Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
  • 15 Institut for Molecular Medecine Finland, University of Helsinki, Helsinki, Finland.
  • 16 Howard Hughes Medical Institute, New York, NY, USA.
  • 17 Collège de France, Paris, France.
  • 18 Imagine Institute, INSERM UMR 1163, Paris, France.
  • 19 Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France. sylvain.latour@inserm.fr.
  • 20 Université Paris Cité, Paris, France. sylvain.latour@inserm.fr.
  • # Contributed equally.
PMID: 38509369 DOI: 10.1038/s41586-024-07213-6
Abstract

Epstein-Barr virus (EBV) Infection can engender severe B cell lymphoproliferative diseases1,2. The primary Infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV Infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 Receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV Infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

Figures
Products