Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases^1,2. 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 subunit^5,6. 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.

EB 病毒 (EBV) 感染可引起严重的 B 细胞淋巴增殖性疾病^1,2。原发感染通常无症状或引起传染性单核细胞增多症 (IM)，这是一种自限性淋巴组织增生性疾病³。据报道，对 EBV 的选择性易感性与损害 T 细胞对 EBV 免疫的遗传突变有关⁴。在此，我们报告了IL27RA中的双等位基因功能丧失变异，该变异是急性和严重的原发性 EBV 感染的基础，但需要最少的治疗即可获得良好的结果。一种突变等位基因 (rs201107107) 在芬兰人群中富集（次要等位基因频率 = 0.0068），纯合时具有严重传染性单核细胞增多症的高风险。IL27RA编码 IL-27 受体 α 亚基^5,6。在没有 IL-27RA 的情况下，T 细胞中 IL-27 对 STAT1 和 STAT3 的磷酸化被消除。在体外研究中，IL-27 对患者细胞中缺乏的 T 细胞受体依赖性 T 细胞增殖⁷发挥协同作用，导致有效的抗 EBV 效应细胞毒性 CD8 ⁺ T 细胞的扩增受损。 IL-27 由 EBV 感染的 B 淋巴细胞产生，IL-27RA–IL-27 自分泌环是维持 EBV 转化的 B 细胞所必需的。这可能解释了 EBV 诱导的病毒性疾病在 IL-27RA 缺乏症患者中的最终有利结果。此外，我们在大多数出现散发性传染性单核细胞增多症和慢性 EBV 感染的个体中发现了中和抗 IL-27 自身抗体。这些结果证明了 IL-27RA–IL-27 在 EBV 免疫中的关键作用，而且还证明了 EBV 劫持了这种防御以促进受感染的转化 B 细胞的扩增。