Co-chaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and b1 integrin function

Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 co-chaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells (ASCs). By analyzing Mzb1 -/- Prdm1 +/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of ASCs in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1 -/- plasmablasts show a reduced activation of b1 integrin, which contributes to the impaired plasmablast differentiation and migration of ASCs to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation. Overall design: Splenic B cells were purified from Mzb1 +/+ Prdm1 +/gfp and Mzb1 -/- Prdm1 +/gfp mice using anti-B220 magnetic beads and cultured in the presence of 25ug/ml LPS. After 4 days, undifferentiated CD138 - Blimp - B cell blasts (Activated B Cells), CD138 - Blimp + (Pre-PB cells), and CD138 + Blimp + (PB cells) were isolated with FACSAria (Becton Dickinson) sort.

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Andreani V, Ramamoorthy S, Pandey A, Lupar E, Nutt SL, Lämmermann T, Grosschedl R