T-bet+ B cells are activated by and control endogenous retroviruses through 
TLR-dependent mechanisms

Rauch, Eileen; Amendt, Timm; Krol, Aleksandra Lopez; Lang, Fabian B.; Linse, Vincent; Hohmann, Michelle; Keim, Ann-Christin; Kreutzer, Susanne; Kawengian, Kevin; Buchholz, Malte; Duschner, Philipp; Grauer, Saskia; Schnierle, Barbara; Ruhl, Andreas; Burtscher, Ingo; Dehnert, Sonja; Kuria, Chege; Kupke, Alexandra; Paul, Stephanie; Liehr, Thomas; Lechner, Marcus; Schnare, Markus; Kaufmann, Andreas; Huber, Magdalena; Winkler, Thomas H.; Bauer, Stefan; Yu, Philipp

doi:10.1038/s41467-024-45201-6

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T-bet⁺ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms

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Kreutzer, Susanne
Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Rauch, E., Amendt, T., Krol, A. L., Lang, F. B., Linse, V., Hohmann, M., et al. (2024). T-bet⁺ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms. NATURE COMMUNICATIONS, 15(1): 1229. doi:10.1038/s41467-024-45201-6.

Cite as: https://hdl.handle.net/21.11116/0000-000E-F532-5

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 function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify 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-gamma levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory 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 host immune response.