show Abstracthide AbstractEndogenous 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. 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. Spleen DNA of a EGT-315 B6 mouse was analyzed to confirm the germline ERV-GFP intgeration. We identified an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of 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.