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; Philipp Yu

doi:10.1038/s41467-024-45201-6

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

Nat Commun. 2024 Feb 9;15(1):1229. doi: 10.1038/s41467-024-45201-6.

Authors

Eileen Rauch^{1

2}, Timm Amendt^{1

3}, Aleksandra Lopez Krol¹, Fabian B Lang¹, Vincent Linse¹, Michelle Hohmann^{1

4}, Ann-Christin Keim¹, Susanne Kreutzer⁵, Kevin Kawengian¹, Malte Buchholz⁶, Philipp Duschner¹, Saskia Grauer¹, Barbara Schnierle⁷, Andreas Ruhl^{1

8}, Ingo Burtscher⁹, Sonja Dehnert¹, Chege Kuria¹⁰, Alexandra Kupke¹¹, Stephanie Paul¹, Thomas Liehr¹², Marcus Lechner¹³, Markus Schnare¹, Andreas Kaufmann¹, Magdalena Huber¹⁴, Thomas H Winkler¹⁰, Stefan Bauer¹, Philipp Yu¹⁵

Affiliations

¹ Institute of Immunology, Philipps-Universität Marburg, 35043, Marburg, Germany.
² CSL Behring Innovation GmbH, Emil-von-Behring-Str. 76, 35041, Marburg, Germany.
³ The Francis Crick Institute, NW1 1AT, London, UK.
⁴ Apollo Ventures Holding GmbH, 20457, Hamburg, Germany.
⁵ Max-Planck-Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
⁶ Department of Gastroenterology, Endocrinology and Metabolism, and Core Facility Small Animal Multispectral and Ultrasound Imaging, Philipps-Universität Marburg, 35043, Marburg, Germany.
⁷ Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany.
⁸ Department of Infection Biology, University Hospital Erlangen, 91054, Erlangen, Germany.
⁹ Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
¹⁰ Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
¹¹ Institute of Virology, Philipps-Universität Marburg, 35043, Marburg, Germany.
¹² Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, 07747, Jena, Germany.
¹³ Center for Synthetic Microbiology, Philipps-Universität Marburg, 35043, Marburg, Germany.
¹⁴ Institute of Sytems Immunology, Center for Tumor and Immunobiology, Philipps-Universität Marburg, 35043, Marburg, Germany.
¹⁵ Institute of Immunology, Philipps-Universität Marburg, 35043, Marburg, Germany. Philipp.Yu@staff.uni-marburg.de.

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.

MeSH terms

Animals
Autoimmune Diseases / genetics
B-Lymphocytes* / immunology
Endogenous Retroviruses* / genetics
Mammals / genetics
Mice

Abstract

MeSH terms

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