Blimp1 controls plasma cell physiology and function. Mus musculus

Antibody-secreting plasma cells are the terminal stage of the B-cell lineage. Plasma cell differentiation requires a major resetting of gene expression to silence the B cell transcriptional program, whilst establishing secretory function and long-term survival. The transcription factors Blimp1 and Irf4 are essential for the initial differentiation of activated B cells to antibody-secreting cells, however their function in mature plasma cells remains elusive. We have found that while Irf4 was essential for plasma cell survival, Blimp1 was dispensable. Blimp1-deficient cells retained the unique plasma cell transcriptional signature, but lost the ability to secrete antibody or to maintain the characteristic size and ultrastructure of plasma cells. Blimp1 was required for full expression of many components of the unfolded protein response (UPR), including Xbp1 and Atf6, as well as for the appropriate processing of Igh mRNA. The overlap of Blimp1 and Xbp1 function was restricted to the UPR genes, with Blimp1 uniquely regulating activity of the mTOR pathway, plasma cell size and morphology. These studies establish Blimp1 as a major regulator of the UPR pathway that is also required for the unique metabolic requirements of plasma cells enabling the secretion of protective antibody. Overall design: RNA-seq was performed on wild type, Blimp1-/- and Xbp1-/- mouse plasma cells. Between two to four biological replicates were generated and sequenced for each sample.