Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies

Inborn errors of immunity (IEIs) represent unique in natura models that uncover key components of immunity in humans, in particular those that predispose to infections. Epstein-Barr virus (EBV) is one of the most common opportunistic infectious agents in humans and is responsible for several diseases, including infectious mononucleosis, nonmalignant and malignant lymphoproliferative disorders, hemophagocytic lymphohistiocytosis, and smooth muscle and epithelial tumors. For most individuals, EBV infection persists for life without pathological consequences. IEIs that do not predispose to EBV infection suggest that innate and humoral responses are not necessary or redundant for the immune response to EBV. IEIs associated with high susceptibility to EBV infection provide unequivocal genetic proof of the central role of CD8+ T cell responses in immunity to EBV. They also highlight the distinct steps and pathways required for, on the one hand, the effector cytotoxic functions of CD8+ T cells and, on the other hand, the expansion and maturation of cytotoxic CD8+ T cells.