Regulation of BCR-mediated Ca mobilization by MIZ1-TMBIM4 safeguards IgG1 GC B cell-positive selection.

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) 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 accumulation. This study uncovers a unique Ig isotype-specific dependency on a hitherto unidentified mechanism in GC-positive selection.