ADAM10 regulates transcription factor expression required for plasma cell function

Abstract

A disintegrin and metalloprotease 10 (ADAM10) is a key regulator of cellular processes by shedding extracellular domains of transmembrane proteins. We have previously demonstrated that deletion of B cell expressed ADAM10 results in changes in lymphoid tissue architecture and impaired germinal center (GC) formation. In this study, mice were generated in which ADAM10 is deleted in B cells following class switch recombination (ADAM10(Δ/Δ)IgG1-cre(+/-) mice). Despite normal GC formation, antibody responses were impaired in ADAM10(Δ/Δ)IgG1-cre(+/-) mice, implicating ADAM10 in post-GC and extrafollicular B cell terminal differentiation. Surprisingly, plasma cell (PC) numbers were normal in ADAM10(Δ/Δ)IgG1-cre(+/-) mice when compared to controls. However, PCs isolated from ADAM10(Δ/Δ)IgG1-cre(+/-) mice exhibited decreased expression of transcription factors important for PC function: Prdm1, Xbp1 and Irf4. Bcl6 is a GC transcriptional repressor that inhibits the PC transcriptional program and thus must be downregulated for PC differentiation to occur. Bcl6 expression was increased in PCs isolated from ADAM10(Δ/Δ)IgG1-cre(+/-) mice at both the mRNA and protein level. These results demonstrate that ADAM10 is required for proper transcription factor expression in PCs and thus, for normal PC function.