Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis
B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.
Authors
- Joachim Pircher (ORCID: https://orcid.org/0000-0002-8890-0884)
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Verena Passerini (ORCID: https://orcid.org/0000-0003-4094-1502)
- Carina Diehl
- Marco Fangazio (ORCID: https://orcid.org/0000-0001-5414-6134)
- Martina Rudelius (ORCID: https://orcid.org/0000-0002-7332-4589)
- Laura Pasqualucci (ORCID: https://orcid.org/0000-0001-6819-7370)
- Govind Bhagat (ORCID: https://orcid.org/0000-0001-6250-048X)
- Stefanie Bärthel (ORCID: https://orcid.org/0000-0001-5986-4864)
- Thomas Engleitner (ORCID: https://orcid.org/0000-0002-7989-681X)
- Maike Kober-Hasslacher
- Mohsen Honarpisheh (ORCID: https://orcid.org/0000-0003-3002-7442)
- Florencia Barrios (ORCID: https://orcid.org/0000-0002-4166-1601)
- Lena Oßwald
- Jonathan Mandelbaum
- Sabrina Bortoluzzi (ORCID: https://orcid.org/0009-0005-1628-3150)
- Sabine Helmrath (ORCID: https://orcid.org/0000-0001-8499-1486)
- Rupert Öllinger (ORCID: https://orcid.org/0000-0002-2292-5982)
- Vedrana Jelenčić (ORCID: https://orcid.org/0000-0001-8606-9313)
- Felix M. Wensveen (ORCID: https://orcid.org/0000-0002-1333-8882)
- David Dominguez-Sola (ORCID: https://orcid.org/0000-0001-9569-8402)
- Oliver Weigert (ORCID: https://orcid.org/0000-0002-0987-7373)
- Thomas Korn (ORCID: https://orcid.org/0000-0002-3633-0955)
- Lisa A. Kraus
- Seren Baygün
- Maciej Lech (ORCID: https://orcid.org/0000-0002-4293-2733)
- Ali Maisam Afzali (ORCID: https://orcid.org/0000-0002-3256-5298)
- Christoph Daniel (ORCID: https://orcid.org/0000-0002-6803-4755)
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Pankaj Singroul (ORCID: https://orcid.org/0000-0001-9855-1828)
- Valeria Soberón
- Vanessa Gölling
- Marc Schmidt‐Supprian (ORCID: https://orcid.org/0000-0002-8543-6166)
- Dieter Saur (ORCID: https://orcid.org/0000-0001-5874-0210)
- Vanna Imširović (ORCID: https://orcid.org/0000-0003-4757-6026)
- Gönül Seyhan (ORCID: https://orcid.org/0000-0002-3879-8009)
- Theodor Zeng (ORCID: https://orcid.org/0009-0001-4842-3681)
- Qurrat Ul Ain (ORCID: https://orcid.org/0000-0003-2398-3698)
- Yuanyuan Chu
Institutions
- University of Rijeka (HR)
- German Cancer Research Center (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Columbia University Irving Medical Center (US)
- German Centre for Cardiovascular Research (DE)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- Cancer Genetics (United States) (US)
- Max Planck Institute of Psychiatry (DE)
- Technical University of Munich (DE)
- Columbia University (US)
- Ludwig-Maximilians-Universität München (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Immunity
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.immuni.2024.11.023
- Citations
- 7
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- H2020 European Research Council