IRF8 regulates myeloid and B lymphoid lineage diversification

Abstract

Interferon regulatory factor 8 (IRF8) is a member of the IRF family of transcription factors whose members play critical roles in interferon (IFN) signaling pathways governing the establishment of innate immune responses by myeloid and dendritic cells. IRF8 is also expressed in lymphoid cells and recent studies have documented its involvement in B cell lineage specification, immunoglobulin light chain gene rearrangement, the distribution of mature B cells into the marginal zone and follicular B cell compartment, and the transcriptional regulation of critical elements of the germinal center reaction. Here we review the contributions of IRF8 to B cell development from hematopoietic stem cells in the bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B cell fate.

Fig. 1

Differentiation of HSC and their progeny in the bone marrow (BM). Targeted deletion of each transcription factors results in interrupted differentiation at a specific stage. HSC (hematopoietic stem cell), MPP (multipotent progenitor), LMPP (lymphoid-primed MPP), ELP (early lymphoid progenitor), CLP (common lymphoid progenitor), Frs. A to E (B lymphocytes of Hardy Fractions A-E). Modified from [1]

Fig. 2

Impaired B cell development in the BM of BXH2 and control mice. (a) BM cells from BXH2 and C57BL/6 mice were stained with antibodies against Lineage panel (Lin), IL-7Rα, c-Kit, and Sca-1. Numbers represent the percentage of total events. (b). BM cells from the same mice were stained for B220, IgM, CD43, BP-1, and HSA. The percentage of B cells falling within each gate is given. Hardy Frs. A to F are indicated. Data are representative of three mice per group. The results from multiple analyses are summarized in Table 1

Fig. 3

A model of IRF8 function in early B cell development. IRF8 modulates expression of PU.1 and together with PU.1 restricts myeloid lineage differentiation while promoting B lineage differentiation by activating expression of EBF, E2A, and PAX5. By associating with IRF4, IRF8 regulates Igκ gene rearrangement and facilitates generation of immature B cells. Modified from [1]