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

Emmanuel Martin, Sarah Winter, Cécile Garcin, Kay Tanita, Akihiro Hoshino, Christelle Lenoir, Benjamin Fournier, Mélanie Migaud, David Boutboul, Mathieu Simonin, Alicia Fernandes, Paul Bastard, Tom Voyer, Anne-Laure Roupie, Yassine Ahmed, Marianne Leruez-Ville, Marianne Burgard, Geetha Rao, Cindy S. Ma, Cécile Masson, Claire Soudais, Capucine Picard, Jacinta Bustamante, Stuart G. Tangye, Nathalie Cheikh, Mikko Seppänen, Anne Puel, Mark Daly, Jean-Laurent Casanova, Bénédicte Neven, Alain Fischer and Sylvain Latour ()
Additional contact information
Emmanuel Martin: INSERM UMR 1163, Imagine Institute
Sarah Winter: INSERM UMR 1163, Imagine Institute
Cécile Garcin: INSERM UMR 1163, Imagine Institute
Kay Tanita: INSERM UMR 1163, Imagine Institute
Akihiro Hoshino: INSERM UMR 1163, Imagine Institute
Christelle Lenoir: INSERM UMR 1163, Imagine Institute
Benjamin Fournier: INSERM UMR 1163, Imagine Institute
Mélanie Migaud: INSERM UMR 1163, Imagine Institute
David Boutboul: Université Paris Cité
Mathieu Simonin: INSERM UMR 1163, Imagine Institute
Alicia Fernandes: Institut Necker Enfants Malades, Necker-Enfants Malades Hospital, APHP
Paul Bastard: Université Paris Cité
Tom Voyer: Université Paris Cité
Anne-Laure Roupie: INSERM UMR 1163, Imagine Institute
Yassine Ahmed: INSERM UMR 1163, Imagine Institute
Marianne Leruez-Ville: Necker-Enfants Malades Hospital
Marianne Burgard: Necker-Enfants Malades Hospital
Geetha Rao: Garvan Institute of Medical Research, Darlinghurst
Cindy S. Ma: Garvan Institute of Medical Research, Darlinghurst
Cécile Masson: INSERM UMR1163, Université de Paris, Imagine Institute
Claire Soudais: INSERM UMR 1163, Imagine Institute
Capucine Picard: INSERM UMR 1163, Imagine Institute
Jacinta Bustamante: Université Paris Cité
Stuart G. Tangye: Garvan Institute of Medical Research, Darlinghurst
Nathalie Cheikh: Hôpital Jean Minjoz, Centre Hospitalo-Universitaire de Besançon
Mikko Seppänen: University of Helsinki and HUS Helsinki University Hospital
Anne Puel: Université Paris Cité
Mark Daly: University of Helsinki
Jean-Laurent Casanova: Université Paris Cité
Bénédicte Neven: Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris (APHP)
Alain Fischer: Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris (APHP)
Sylvain Latour: INSERM UMR 1163, Imagine Institute

Nature, 2024, vol. 628, issue 8008, 620-629

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07213-6

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