Dual role of IL-27 in Epstein-Barr virus infection revealed by IL27RA deficiency

Epstein-Barr virus (EBV) infection can engender severe B-cell lymphoproliferative diseases. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV. Herein, we report bi-allelic loss-of-function mutations variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favorable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (MAF=0.0068) and carried a high risk of severe IM when homozygous. IL27RA codes for the a subunit of the receptor of IL-27. In the absence of IL27RA, phosphorylation of STAT1 and STAT3 in response to IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on TCR-dependent T cell proliferation that is abolished 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 IL27RA-IL-27 autocrine loop is required for maintenance of EBV-transformed B cells. This potentially explains the eventual favorable outcome of the EBV-induced viral disease in IL27RA-deficient patients. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic IM and chronic EBV infection. Collectively, these results demonstrate the critical role of IL27RA-IL-27 axis in T cell immunity to EBV, but also the hijacking of this defense by EBV to promote expansion of infected B cells. To investigate transcriptomic impact associated with IL27RA-deficiency, gene expression (including EBV genes) of two control LCLs and two IL27RA-deficient LCLs issued from two patients P1.1 and P.2 were analysed in response to IL-27 (Stim_IL27) compared to non-stimulated cells (Basal).