Activation, control and T-bet+ B cell-mediated immune surveillance of endogenous retroviruses

Abstract Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their role as anti-cancer immune targets or drivers of autoimmune disease. Here, we generated mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the murine germline. This enabled us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identified an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on T-bet+ B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the hosts immune response.