A genome wide CRISPR screen reveals novel determinants of long-lived plasma cell secretory capacity

Abstract Plasma cell subsets vary in their lifespans and ability to sustain humoral immunity. We conducted a genome-wide CRISPR-Cas9 screen in myeloma cells for factors that promote surface expression of CD98, a marker of longevity in mouse plasma cells. A large fraction of genes found to promote CD98 expression in this screen are involved in secretory and other vesicles, including subunits of the V-type ATPase complex. Genetic ablation and chemical inhibition of V-type ATPases in myeloma cells and primary plasma cells, respectively, reduced antibody secretion. Mouse and human long-lived plasma cells had greater numbers of acidified vesicles than their short-lived counterparts, and this correlated with increased antibody secretory capacity. The screen also revealed a requirement for the signaling adapter MYD88 in CD98 expression. Plasma cell-specific deletion of Myd88 led to reduced survival and antibody secretion by antigen-specific cells in vivo and unresponsiveness to BAFF and APRIL ex vivo. These data reveal novel regulators that link plasma cell secretory capacity and lifespan. Summary Long-lived plasma cells rely on V-type ATPases, PI4K, DDX3X, and MYD88 signals for maximal secretory capacity and survival Competing Interest Statement Sana Biotechnology has licensed intellectual property of DB and Washington University in St. Louis. Inograft biotherapeutics and Jasper Therapeutics have licensed intellectual property of DB and Stanford University. D.B. is on the scientific advisory board for Hillevax. DB is a scientific co-founder of Aleutian Therapeutics. All other authors report no conflicts of interest. Footnotes New data in Figure 9 to show that APRIL and BAFF enhance antibody secretion by plasma cells through a MYD88-dependent mechanism.