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- Title
Regulation of BCR-mediated Ca<sup>2+</sup> mobilization by MIZ1-TMBIM4 safeguards IgG1<sup>+</sup> GC B cell–positive selection.
- Authors
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
- 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
- Subjects
B cell receptors; HUMORAL immunity; B cells; IMMUNOGLOBULIN M; ANTIBODY formation
- Publication
Science Immunology, 2024, Vol 9, Issue 94, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adk0092