The LRF transcription factor regulates mature B cell development and the germinal center response in mice
Nagisa Sakurai, … , Ravi Bhatia, Takahiro Maeda
Nagisa Sakurai, … , Ravi Bhatia, Takahiro Maeda
Published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2583-2598. https://doi.org/10.1172/JCI45682.
View: Text | PDF
Research Article Immunology

The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Abstract

B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cell–specific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies.

Authors

Nagisa Sakurai, Manami Maeda, Sung-Uk Lee, Yuichi Ishikawa, Min Li, John C. Williams, Lisheng Wang, Leila Su, Mai Suzuki, Toshiki I. Saito, Shigeru Chiba, Stefano Casola, Hideo Yagita, Julie Teruya-Feldstein, Shinobu Tsuzuki, Ravi Bhatia, Takahiro Maeda

×

Figure 4

Lrf is required for GCB cell proliferation and survival.

Options: View larger image (or click on image) Download as PowerPoint
Lrf is required for GCB cell proliferation and survival. (A) GCB cells w...
(A) GCB cells were isolated from spleens of LrfFlox/+ mb-1 Cre+ and LrfFlox/Flox mb-1 Cre+ mice and gene expression microarray analysis performed. A total of 706 probes were downregulated and 812 probes were upregulated more than 1.5-fold in LRF-deficient GCB cells. (B) Representative results of GSEA analysis. NES, normalized enrichment score; FDR-q, false discovery rate q value. (C) Mice were immunized with NP-CGG. On day 7 after immunization, EdU was intraperitoneally injected 5 hours before analysis. FACS analysis of EdU incorporation in GCB cells (B220+CD19+CD38–FAS+) and non-GCB cells (B220+CD19+CD38+FAS–). (D) Graphs show proportions of EdU-positive (left) and S phase (right) cells in GC–B cells. (E) Time-course analysis of absolute GCB cell numbers. x axis shows days after NP-CGG immunization. (F) Dot graph demonstrates the proportion of Cxcr4hi cells within GCB cells. (G) Mice were immunized with SRBCs, and apoptosis of GCB cells was measured by active caspase-3 staining (left) and cleaved PARP staining (right) 7 days after immunization. Horizontal black bars indicate average value; error bars indicate SD.