MiR-148a controls plasma cell differentiation and survival

Abstract

Abstract microRNAs (miRNAs) are critical regulators of central and Ag-driven B cell development. However, it is unknown whether miRNAs regulate the differentiation of B cells into plasma cells (PCs) and control the survival of long-lived PCs. We recently showed that miR-148a, the most abundantly expressed miRNA in PCs, is upregulated in activated B cells and promotes in vitro plasmablast differentiation and survival by targeting Bach2, MiTF, PTEN and Bim. To investigate if miR-148a supports PC differentiation in vivo, we established a conditional B cell-specific miR-148a knock-out mouse. Non-immunized mice showed a significant decrease in serum Ig, antibody-secreting cells (ASC) and splenic PCs. 28d after boost, TNP-KLH-immunized 148a-KO mice had lower serum TNP-IgG and decreased numbers of splenic ASCs and bone marrow (BM) PCs. To ask whether miR-148a controls PC survival, we generated tamoxifen-inducible miR-148a deficient mice. Tamoxifen-mediated miR-148a deletion, 28 days after boost with TNP-KLH, resulted in reduced numbers of plasmablasts and IgG-ASCs in the spleen and of resting PCs and IgG-ASCs in BM. In parallel, increased numbers of resting PCs were found in the blood, indicating a possible egress from survival niches. These findings support the hypothesis that miR-148a controls the differentiation of B cells into plasmablasts as well as the survival of long-lived PCs. We will now identify the underlying mechanism by a biosystems approach utilizing transcriptome and proteome profiles of fresh follicular B cells and BM PCs. Proteome analysis was done in collaboration with the Warscheid lab at the University of Freiburg.