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Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TMBIM4 safeguards IgG1+ GC B cell–positive selection.
- Source :
- Science Immunology; 2024, Vol. 9 Issue 94, p1-16, 16p
- Publication Year :
- 2024
-
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<superscript>+</superscript> B cells over IgM<superscript>+</superscript> 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<superscript>+</superscript> GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1<superscript>+</superscript> GC B cell survival during positive selection, whereas IgM<superscript>+</superscript> GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca<superscript>2+</superscript>) mobilization downstream of B cell receptor (BCR) signaling in IgG1<superscript>+</superscript> B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1<superscript>+</superscript> GC cell death caused by excessive Ca<superscript>2+</superscript> 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)<superscript>+</superscript> B cells within germinal centers (GCs) promotes potent humoral immune responses, yet how the positive selection of IgG1<superscript>+</superscript> 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<superscript>+</superscript> 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<superscript>+</superscript> GC B cells during positive selection. —Hannah Isles [ABSTRACT FROM AUTHOR]
- Subjects :
- B cell receptors
HUMORAL immunity
B cells
IMMUNOGLOBULIN M
ANTIBODY formation
Subjects
Details
- Language :
- English
- ISSN :
- 24709468
- Volume :
- 9
- Issue :
- 94
- Database :
- Complementary Index
- Journal :
- Science Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 177039588
- Full Text :
- https://doi.org/10.1126/sciimmunol.adk0092