The primary and secondary immune response to Epstein-Barr virus infection of human tonsil organoids

Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis (IM) and is associated with cancer and autoimmune disease. Humans are the only natural host for EBV and humanised mice are the only small animal model of infection. Consequently, although IM in adults following primary infection has been studied intensively, little is known about the virological and immunological events that occur during the initial phases of the virus-host interaction. EBV is usually transmitted via saliva exchange, and is thought to infect its main host, the human B cell, in mucosal secondary lymphoid tissues, such as the tonsils. Thus, to address this gap in knowledge, we have studied the immune response to EBV infection using tonsil organoids as a model that allows us to address the greater systemic complexity present at the site of infection in the oropharynx. EBV infection is efficiently controlled when the tonsils are derived from "virus-experienced" individuals and CD8+ memory T lymphocytes expressing CD103 play a leading role in this immune response. In contrast, in primary infections, immune control of lymphoblastoid cell proliferation is much less effective, and a key factor restricting the immune response is the secretion of the immunomodulatory viral IL-10 molecule. These results highlight the importance of the host cytotoxic response at the site of infection and demonstrate that immune evasion molecules appear to be crucial for EBV-infected B cells to elude the local immune response and so disseminate the infection throughout the organism.