IFN Regulatory Factor 8 Restricts the Size of the Marginal Zone and Follicular B Cell Pools

Abstract

Transcriptional control of marginal zone (MZ) and follicular (FO) B cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B cells. Mice with a conventional knockout of Irf8 (IRF8–/–) or a point mutation in the IRF association domain of IRF8 had increased numbers of MZ B cells. To determine the B cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numbers of MZ and FO B cells compared with controls. The FO B cells of CKO mice exhibited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal Ab responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B cells but has little effect on B cell function.

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

“…1C), which do not express IRF8 (35). As noted previously with Irf8 −/− normal background mice (36,37), IRF8-deficient NZB mice also showed expansion of marginal zone and CD21 low CD23 + follicular and transitional B cells, but total B-cell and T-cell numbers were unchanged (data not shown).…”

“…However, as reported previously (37) and reproduced here with IRF8-deficient NZB mice, humoral responses to exogenous antigens remain unmodified. Furthermore, we have shown that Irf8 −/− B cells mounted normal in vitro responses to TLR7 and TLR9 ligands, which could be enhanced with IFN-α.…”

“…It is of interest that, in contrast to reductions or even absence of autoantibodies, responses to conventional T-dependent and T-independent antigens were of normal magnitude and quality in Irf8 −/− NZB mice, as reported for normal background mice with B-cell-specific conditional Irf8 deletion (37). A possible explanation for this finding is that with lupus-associated autoantigens, adjuvanticity is provided by endosomal TLR engagement by selfnucleic acids, whereas adjuvanticity of complete (CFA) and incomplete (IFA) Freund's adjuvants, or alum in response to conventional exogenous antigens is mediated by endosomal TLRindependent pathways (46)(47)(48).…”

Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma

“…12,15,24 However, compared with other hematologic malignancies, like diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, acute lymphoblastic anemia, or multiple myeloma, the current understanding of the incidence of recurrent gene mutations and the interplay of gene mutations and aCNA/ LOH and cnLOH in FL is in its early stages and largely incomplete. 3,[25][26][27][28][29][30][31][32][33][34][35] The discovery of genes mutated in various forms of cancer has further advanced our understanding of the specific pathogenetic mechanisms that operate in cancer cell subtypes. Recently, as a result of the study of DLBCL, 2 novel high-frequency mutated genes (MLL2 and CREBBP) in non-Hodgkin lymphoma (NHL) were identified.…”

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

“…Analyses of B lineage cells showed that IRF8 contributes to a series of transcriptional networks affecting the earliest stages of lineage commitment and specification in the bone marrow (12), rearrangements at the immunoglobulin (Ig) locus (13), and distribution of mature cells into splenic B cell subcompartments (14). IRF8 was shown to exert its influences on the germinal center (GC) reaction, class switch recombination, and plasma cell development through partnering with PU.1 and IRF4 to promote the activation of Aicda and Bcl6, genes central to the maintenance of the B cell program, while repressing genes such as Prdm1 that promote terminal differentiation (15,16).…”