Regulation of BCR-mediated Ca 2+ mobilization by MIZ1-TMBIM4 safeguards IgG1 + GC B cell–positive selection

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 (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.