| First Author | Zhang L | Year | 2024 |
| Journal | Sci Immunol | Volume | 9 |
| Issue | 94 | Pages | eadk0092 |
| PubMed ID | 38579014 | Mgi Jnum | J:350805 |
| Mgi Id | MGI:7625738 | Doi | 10.1126/sciimmunol.adk0092 |
| Citation | Zhang L, et al. (2024) Regulation of BCR-mediated Ca(2+) mobilization by MIZ1-TMBIM4 safeguards IgG1(+) GC B cell-positive selection. Sci Immunol 9(94):eadk0092 |
| abstractText | 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 (Ca(2+)) 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 Ca(2+) accumulation. This study uncovers a unique Ig isotype-specific dependency on a hitherto unidentified mechanism in GC-positive selection. |
