Epstein-Barr virus infection can engender severe B-cell lymphoproliferative disorders in immunocompromised individuals. In immunocompetent individuals, the primary infection is often asymptomatic or causing infectious mononucleosis, a self-limiting lymphoproliferative disorder. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV. Herein, the inventors report bi-allelic loss-offunction mutations in IL-27RA in humans that underlie an acute and severe primary EBV infection but with a spontaneous favorable outcome. In the absence of IL27RA, STAT1 and STAT3 phosphorylation in response to IL-27 is abolished in T cells of patients. Upon EBV infection, the inventors found that IL-27 is produced by infected B lymphocytes and IL27RAIL-27 interaction is required for in vitro maintenance and expansion of EBV-transformed B cells, potentially explaining the favorable outcome of the EBV viral disease in IL27RAdeficient patients. In addition, the inventors identified neutralizing anti-IL27 autoantibodies in individuals who developed sporadic infectious mononucleosis, thus possibly phenocopying the IL27RA deficiency. Collectively, these results demonstrate the critical role of IL27-IL27RA axis in immunity to EBV, but also the hijacking of this defense by EBV to promote expansion of infected cells. The IL27-IL27RA could therefore represent a novel therapeutic target to inhibit EBV-driven B lymphoproliferative diseases.