Transcription Factor ICSBP/IRF8 Regulates B Cell Development at Multiple Checkpoints.

Abstract

The generation of lymphoid and myeloid lineage cells from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental and functional aspects. Interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF8) is a transcription factor known to regulate the differentiation of macrophages, granulocytes, and dendritic cells. Our recent findings that IRF8 transcripts and protein are highly expressed in germinal center (GC) B cells suggest that IFR8 may also play a role in normal B cell development. In IRF8 deficient mice, the number of early B lineage cells (pre-pro-B) was reduced by 5-fold, indicating a defect in early B lineage commitment. While the numbers of late pre-B and immature B cells were moderately reduced (~2-fold), recirculating mature B cells were almost undetectable in the bone marrow of mutant mice. This deficiency in early stage B cells is correlated with increased expression of PU.1, a crucial transcription factor for myeloid and lymphoid lineage specification. Interestingly, the number of splenic transitional 1 (T1) cells was slightly increased but the numbers of T2 and follicular (FO) B-2 cells were moderately decreased in mutant mice. This indicates that positive selection of T2 cells into the mature B-2 pool is regulated by IRF8. The marginal zone (MZ) B cell and peritoneal CD11b+ B-1b cell compartments were also slightly expanded in IRF8 knockout mice. Overall, these results provide compelling evidence that IRF8 regulates B cell differentiation and function at multiple stages.