Zhang, Lingling;
Toboso-Navasa, Amparo;
Gunawan, Arief;
Camara, Abdouramane;
Nakagawa, Rinako;
Finsterbusch, Katja;
Chakravarty, Probir;
... Calado, Dinis Pedro; + view all
(2024)
Regulation of BCR-mediated Ca²⁺ mobilization by MIZ1-TMBIM4 safeguards IgG1⁺ GC B cell–positive selection.
Science Immunology
, 9
(94)
, Article eadk0092. 10.1126/sciimmunol.adk0092.
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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.
| Type: | Article |
|---|---|
| Title: | Regulation of BCR-mediated Ca²⁺ mobilization by MIZ1-TMBIM4 safeguards IgG1⁺ GC B cell–positive selection |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciimmunol.adk0092 |
| Publisher version: | https://doi.org/10.1126/sciimmunol.adk0092 |
| Language: | English |
| Additional information: | This version is the author-accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | IgG1, germinal center; B cell; positive selection, apoptosis, calcium, IP3 receptor, CRISPR25 Cas9, Miz1 (Zbtb17); Tmbim4 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10190681 |
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