Regulation of BCR-mediated Ca²⁺mobilization by MIZ1-TIMBIM4 safeguards IgG1⁺GC B cell positive selection

Summary The transition from IgM to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential accumulation of IgG + B cells over IgM + B cells. However, it is not known whether the positive selection of the different immunoglobulin isotypes within GCs varies in its dependency on specific transcriptional mechanisms. Here, we identified IgG1 + GC B cell transcription factor dependency using CRISPR-Cas9 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 mediated Ca 2+ mobilization downstream of IgG1. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1 + GC cell death caused by excessive Ca 2+ accumulation. This study uncovers a unique immunoglobulin isotype-specific dependency, on a hitherto unidentified mechanism in GC positive selection.