The Xbp1-regulated transcription factor Mist1 restricts antibody secretion by restraining Blimp1 expression in plasma cells

Abstract

Antibody secretion by plasma cells provides acute and long-term protection against pathogens. The high secretion potential of plasma cells depends on the unfolded protein response, which is controlled by the transcription factor Xbp1. Here, we analyzed the Xbp1-dependent gene expression program of plasma cells and identified Bhlha15 (Mist1) as the most strongly activated Xbp1 target gene. As Mist1 plays an important role in other secretory cell types, we analyzed in detail the phenotype of Mist1-deficient plasma cells in Cd23-Cre Bhlha15fl/fl mice under steady-state condition or upon NP-KLH immunization. Under both conditions, Mist1-deficient plasma cells were 1.4-fold reduced in number and exhibited increased IgM production and antibody secretion compared to control plasma cells. At the molecular level, Mist1 regulated a largely different set of target genes compared with Xbp1. Notably, expression of the Blimp1 protein, which is known to activate immunoglobulin gene expression and to contribute to antibody secretion, was 1.3-fold upregulated in Mist1-deficient plasma cells, which led to a moderate downregulation of most Blimp1-repressed target genes in the absence of Mist1. Importantly, a 2-fold reduction of Blimp1 (Prdm1) expression was sufficient to restore the cell number and antibody expression of plasma cells in Prdm1Gfp/+Cd23-Cre Bhlha15fl/fl mice to the same level seen in control mice. Together, these data indicate that Mist1 restricts antibody secretion by restraining Blimp1 expression, which likely contributes to the viability of plasma cells.

Mime-seq 2.0: a method to sequence microRNAs from specific mouse cell types

“…As the main advantage of mime-seq is to facilitate miRNA profiling in rare cell populations, it is important to assess its sensitivity. To this end, we used the Bhlha15 -Cre line for conditional activation of HENMT1 ∆C -T6B expression in plasma cells (PCs), as the Bhlha15 (Mist1) gene is specifically expressed in PCs within the hematopoietic system (Wöhner et al, 2022 ). Seven days after immunization with sheep red blood cells, GFP + PCs (CD138 + TACI + ) were isolated from the spleen of Bhlha15 -Cre R26 LSL-HenT6B/LSL-HenT6B mice by flow-cytometric sorting (Fig.…”

Single‐cell atlas reveals a distinct immune profile fostered by T cell‐B cell crosstalk in triple negative breast cancer

“…Cells in Path I highly expressed several genes encoding heat shock proteins (HSPs), such as Hsp70 members ( HSPA1 and HSPA8 ) [ 39 ] and Hsp90 members ( HSP90AA1 and HSP90AB1 ) [ 40 ], which acted as important immunomodulators in antigen presentation and T cell activation [ 41 ]. Cells in Path II highly expressed the genes associated with antibody synthesis and humoral immunity, such as XBP1 [ 42 ] and MZB1 [ 43 ], and genes encoding immunoglobulins. In addition, PPI network analyses based on differentially expressed TFs of each path suggested that some genes might be the key regulatory TFs in B cell differentiation, such as STAT1 in Path II, MYC in Path I and JUN in Pre‐branch (Supplementary Figure S4C ).…”

Mime-seq 2.0: a method to sequence microRNAs from specific mouse cell types

“…As the main advantage of mime-seq is to facilitate miRNA profiling in rare cell populations, it is important to assess its sensitivity. As the Bhlha15 (Mist1) gene is specifically expressed in plasma cells (PCs) within the hematopoietic system 24 , we used the Bhlha15 -Cre line for conditional activation of HENMT ΔC -T6B expression in splenic PCs. Seven days after immunization with sheep red blood cells, GFP + PCs (CD138 + TACI + ) were isolated from the spleen of Bhlha15 -Cre R26 LSL-HenT6B/LSL-HenT6B mice by flow-cytometric sorting ( Extended Data Fig.…”