Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency
成果类型：
Article
署名作者：
Martin, Emmanuel; Winter, Sarah; Garcin, Cecile; Tanita, Kay; Hoshino, Akihiro; Lenoir, Christelle; Fournier, Benjamin; Migaud, Melanie; Boutboul, David; Simonin, Mathieu; Fernandes, Alicia; Bastard, Paul; Le Voyer, Tom; Roupie, Anne-Laure; Ben Ahmed, Yassine; Leruez-Ville, Marianne; Burgard, Marianne; Rao, Geetha; Ma, Cindy S.; Masson, Cecile; Soudais, Claire; Picard, Capucine; Bustamante, Jacinta; Tangye, Stuart G.; Cheikh, Nathalie; Seppanen, Mikko; Puel, Anne; Daly, Mark; Casanova, Jean-Laurent; Neven, Benedicte; Fischer, Alain; Latour, Sylvain
署名单位：
Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Cochin - APHP; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Garvan Institute of Medical Research; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Rockefeller University; Universite Marie et Louis Pasteur; CHU Besancon; University of Helsinki; University of Helsinki; University of Helsinki; Howard Hughes Medical Institute; Universite PSL; College de France; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite
刊物名称：
Nature
ISSN/ISSBN：
0028-5272
DOI：
10.1038/s41586-024-07213-6
发表日期：
2024-04-18
页码：
620-629
关键词：
chronic mucocutaneous candidiasis
of-function mutations
induced gene 3
humans reveals
growth-factor
t-cells
cytokine
autoantibodies
expression
receptor
摘要：
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. IL-27RA-IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein-Barr virus to promote the expansion of infected transformed B cells