Abstract
OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation.
Highlights
The development of B lymphocytes is under precise control by a large number of transcription factors acting at distinct stages to promote cellular differentiation, survival or proliferation
To define whether tightly regulated expression of OBF1 is critical for B cell development and/or function we generated transgenic mice expressing an HA epitope-tagged OBF1 cDNA under the control of an immunoglobulin variable heavy chain promoter and m heavy chain enhancer (Fig. 1A)
This misregulated expression pattern of OBF1 has a dramatic impact on mature B cells in the spleen, as the mice have an impaired T-dependent immune response accompanied with a strong reduction of follicular B cells (Fig. 1Band E, F)
Summary
The development of B lymphocytes is under precise control by a large number of transcription factors acting at distinct stages to promote cellular differentiation, survival or proliferation. OBF1 mutant mice have a severely impaired T cell dependent (TD) humoral immune response with low levels of isotype-switched secondary immunoglobulins (IgGs) and OBF12/2 follicular B cells fail to form germinal centers (GCs) [11,12,16,17]. This absence of GCs may be due in part to the impaired expression of the Ets factor SpiB, which we showed to be a direct target of OBF1 in B cells [18] and is itself important for GC formation [19]. In a pure C57BL/6 genetic background OBF1 is crucial for marginal zone (MZ) B cells [20]
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