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 (ADAM10Δ/ΔIgG1-cre+/− mice). Despite normal GC formation, antibody responses were impaired in ADAM10Δ/ΔIgG1-cre+/− mice, implicating ADAM10 in post-GC and extrafollicular B cell terminal differentiation. Surprisingly, plasma cell (PC) numbers were normal in ADAM10Δ/ΔIgG1-cre+/− mice when compared to controls. However, PCs isolated from ADAM10Δ/ΔIgG1-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 ADAM10Δ/ΔIgG1-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.
Highlights
Key features of antibody-mediated immune responses are the generation of antigen-specific plasma cells (PCs) and memory B cells
We show that in spite of normal PC numbers, mRNA expression levels of transcription factors important for PC development, Prdm1, xbp1 and Irf4 were altered in PCs isolated from ADAM10D/DIgG1cre+/2 mice
In order to determine whether A disintegrin and metalloprotease 10 (ADAM10) plays a role in PC development or if the impairment in antibody production observed in ADAM10B2/2 mice was secondary to changes in architecture, we crossed ADAM10D/D mice with IgG1-cre transgenic mice and generated ADAM10D/DIgG1-cre+/2mice [20]
Summary
Key features of antibody-mediated immune responses are the generation of antigen-specific plasma cells (PCs) and memory B cells. The transcription factors that are generally required for PC differentiation are B lymphocyteinduced maturation protein 1 (Blimp1), interferon regulatory factor 4 (IRF4) and X-box binding protein 1 (Xbp1) [4,5,6,7]. Downregulation of Bcl and Blimp upregulation is essential for PC differentiation and optimal humoral responses [1,2,11]. Consistent with this idea, study of transgenic mice that constitutively express Bcl in B cells showed a decreased number of class-switched PCs [3,12]
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