The LRF transcription factor regulates mature B cell development and the germinal center response in mice
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
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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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 2

LRF is necessary for GC formation.

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LRF is necessary for GC formation. (A) FACS profiles of splenic GC cells...
(A) FACS profiles of splenic GC cells. Control (LrfFlox/+ mb-1 Cre+) and KO (LrfFlox/Flox mb-1 Cre+) mice were intraperitoneally injected with NP-CGG. Splenocytes were harvested 2 weeks after immunization and analyzed with multi-color FACS using the indicated cell surface markers. (B) There were significantly fewer GC cells in LrfFlox/Flox mb-1 Cre+ mice. Dot graphs demonstrate proportions (left) and absolute numbers (right) of GC cells (DAPI–B220+CD19+CD38–FAS+) of each genotype. Cre-negative control (n = 12), Lrf heterozygous (Flox/+ Cre+; n = 7), and B cell–specific Lrf KO (Flox/Flox Cre+; n = 10) mice were analyzed. Horizontal black bars indicate average value; error bars indicate SD. (C) IHC analysis of secondary lymphoid organs. GC formation in Peyer patches (bottom) and spleens (top) was examined by IHC. GCs are recognized as clusters of Bcl6-positive cells. Original magnification, ×40 (spleen); ×100 (Peyer patches). (D) FACS profiles of splenic GCB cells for control, Lrf KO (LrfFlox/Flox mb-1 Cre+), Notch2 KO (Notch2Flox/Flox mb-1 Cre+), and Lrf/Notch2 double-KO (LrfFlox/FloxNotch2Flox/Flox mb-1 Cre+) mice. The reduction in GCB cells was not recovered by loss of the Notch2 gene. (E) Frequencies and absolute numbers of GCB cells for each genotype. Horizontal black bars indicate average value; error bars indicate SD.