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Wando Mount Pleasant Library
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Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TMBIM4 safeguards IgG1+ GC B cell–positive selection.
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- Author(s): Zhang, Lingling; Toboso-Navasa, Amparo; Gunawan, Arief; Camara, Abdouramane; Nakagawa, Rinako; Finsterbusch, Katja; Chakravarty, Probir; Newman, Rebecca; Zhang, Yang; Eilers, Martin; Wack, Andreas; Tolar, Pavel; Toellner, Kai-Michael; Calado, Dinis Pedro
- Source:
Science Immunology; 2024, Vol. 9 Issue 94, p1-16, 16p- Subject Terms:
- Source:
- Additional Information
- Abstract: The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG+ B cells over IgM+ B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1+ GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1+ GC B cell survival during positive selection, whereas IgM+ GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca2+) mobilization downstream of B cell receptor (BCR) signaling in IgG1+ B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1+ GC cell death caused by excessive Ca2+ accumulation. This study uncovers a unique Ig isotype–specific dependency on a hitherto unidentified mechanism in GC-positive selection. Editor's summary: Positive selection of high-affinity immunoglobulin G (IgG)+ B cells within germinal centers (GCs) promotes potent humoral immune responses, yet how the positive selection of IgG1+ GC B cells is regulated is not well defined. By studying mice with a GC B cell–specific deletion of the transcription factor MIZ1, Zhang et al. identified that MIZ1 was required for affinity maturation of IgG1+ GC B cells and high-affinity antibody production. MIZ1 promoted expression of the gene encoding the anti-apoptotic protein TMBIM4, which limited calcium mobilization downstream of BCR activation, and prevented mitochondrial dysfunction and cell death. These findings demonstrate that MIZ1 expression ensures the survival of IgG1+ GC B cells during positive selection. —Hannah Isles [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Science Immunology is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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