High frequency of lytic EBV-IAV cross-reactive CD8 T cells in EBV sero-negative adults (105.47)

Abstract

Abstract The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a life-long infection. The clinical presentation of EBV infection can range from asymptomatic to severe, occasionally fatal, acute infectious mononucleosis (IM). There is also a strong causal relationship between EBV infection and common malignancies, including carcinoma’s, and Burkitt’s lymphoma. However it is unknown why 5-10% of adults remain EBV-sero-negative (EBV-SN), despite the fact the virus infects the vast majority of the population and is actively shed at high titers even during chronic infection. Here, we show that EBV-SN HLA-A2+ adults possess cross-reactive IAV-GIL/EBV-GLC memory CD8 T-cells that show highly unique properties. These IAV-GIL crossreactive cells preferentially expand, and produce cytokines to, EBV antigens with high avidity. Additionally they are capable of lysing EBV-infected targets and show the potential to enter the mucosal epithelial tissue where infection is thought to initiate. They also possess a T-cell receptor (TCR) repertoire that differs by both organization and CDR3 usage from that in EBV-seropositive (EBV-SP) donors. Our results imply that heterologous immunity may protect EBV-SN adults against the establishment of productive EBV infection, and thus be the first demonstration of heterologous immunity between unrelated pathogens in sero-negative human subjects.