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

Abstract

SummaryThe 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 Ca2+mobilization downstream of IgG1. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction-induced IgG1+GC cell death caused by excessive Ca2+accumulation. This study uncovers a unique immunoglobulin isotype-specific dependency, on a hitherto unidentified mechanism in GC positive selection.