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

Eileen Rauch, Timm Amendt, Aleksandra Lopez Krol, Fabian B. Lang, Vincent Linse, Michelle Hohmann, Ann-Christin Keim, Susanne Kreutzer, Kevin Kawengian, Malte Buchholz, Philipp Duschner, Saskia Grauer, Barbara Schnierle, Andreas Ruhl, Ingo Burtscher, Sonja Dehnert, Chege Kuria, Alexandra Kupke, Stephanie Paul, Thomas Liehr, Marcus Lechner, Markus Schnare, Andreas Kaufmann, Magdalena Huber, Thomas H. Winkler, Stefan Bauer and Philipp Yu ()
Additional contact information
Eileen Rauch: Philipps-Universität Marburg
Timm Amendt: Philipps-Universität Marburg
Aleksandra Lopez Krol: Philipps-Universität Marburg
Fabian B. Lang: Philipps-Universität Marburg
Vincent Linse: Philipps-Universität Marburg
Michelle Hohmann: Philipps-Universität Marburg
Ann-Christin Keim: Philipps-Universität Marburg
Susanne Kreutzer: Max-Planck-Institute for Heart and Lung Research
Kevin Kawengian: Philipps-Universität Marburg
Malte Buchholz: Philipps-Universität Marburg
Philipp Duschner: Philipps-Universität Marburg
Saskia Grauer: Philipps-Universität Marburg
Barbara Schnierle: Paul-Ehrlich-Institut
Andreas Ruhl: Philipps-Universität Marburg
Ingo Burtscher: Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München
Sonja Dehnert: Philipps-Universität Marburg
Chege Kuria: Friedrich-Alexander Universität Erlangen-Nürnberg
Alexandra Kupke: Philipps-Universität Marburg
Stephanie Paul: Philipps-Universität Marburg
Thomas Liehr: Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics
Marcus Lechner: Philipps-Universität Marburg
Markus Schnare: Philipps-Universität Marburg
Andreas Kaufmann: Philipps-Universität Marburg
Magdalena Huber: Philipps-Universität Marburg
Thomas H. Winkler: Friedrich-Alexander Universität Erlangen-Nürnberg
Stefan Bauer: Philipps-Universität Marburg
Philipp Yu: Philipps-Universität Marburg

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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-γ 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.

Date: 2024
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DOI: 10.1038/s41467-024-45201-6

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