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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.
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Research Article Immunology

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

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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 8

Dimer formation is required for LRF function in B cells.

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Dimer formation is required for LRF function in B cells.
(A) Transrepres...
(A) Transrepression assays in Lrf–/–p19Arf–/– immortalized MEFs transfected with empty vector, WT Lrf, or dimerization-deficient (I20A) Lrf expression vector along with mouse p19Arf luciferase-based reporter. Data represent mean with SD. (B) Growth curves of Lrf+/+ and Lrf–/– MEFs after infection with empty, WT, or I20A Lrf retroviral vector. y axis shows relative cell numbers measured by attenuance (D) at 595 nm. Error bars indicate SD. (C) Schematic representation of the CSEμmarCD19-IRES-GFP vector. (D) BM HSCs were harvested from CD45.2+ LrfFlox/Flox mb-1 Cre+ mice after 5-FU injection, infected with B cell–specific lentivirus, and transferred to CD45.1+ recipient mice. The recipient mice were immunized 2 months after transplantation and GC formation analyzed 7 days after immunization. (E) Representative FACS profiles of GCB cell development in recipient mice. GFP was predominantly expressed in B cells (B220+CD19+), confirming B cell–specific transgene expression. Only WT-Lrf–transduced CD45.2+ donor B cells (from LrfFlox/Flox mb-1 Cre+ mice) could give rise to GCB cells upon immunization. (F) Bar graph showing ratios between GFP-negative and -positive GCB cells within total CD45.2+ GCB cells for each group (4 mice per group). Error bars indicate SD. (G) Key roles of LRF in mature B cell lineage fate and GC reaction. LRF may regulate FOB versus MZB lineage fate determination by counteracting the Notch2/Dll1 pathway, while it regulates GCB cell proliferation and survival by repressing ARF.
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