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 July 1, 2011; First published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2583-2598. https://doi.org/10.1172/JCI45682.
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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

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Figure 4

Lrf is required for GCB cell proliferation and survival.

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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.