Interferon regulatory factor 4 and 8 in B-cell development

Abstract

Interferon regulatory factor 4 (IRF4) and 8 are members of the interferon regulatory factor family of transcription factors and have been shown to be essential for the development and function of T cells, macrophages and dendritic cells. A series of recent studies have further demonstrated critical functions for IRF4 and 8 at several stages of B-cell development including pre-B-cell development, receptor editing, germinal center reaction and plasma cell generation. Collectively, these new studies provide molecular insights into the function of IRF4 and 8 and underscore a requirement for IRF4 and 8 throughout B-cell development. This review focuses on the recent advances on the roles of IRF4 and 8 in B-cell development.

Figure 1. IRF4 and 8 are required throughout B cell development

IRF4 and 8 function redundantly during pre-B cell development. However, IRF4, but not IRF8, is uniquely required for receptor editing at the immature B cell stage. IRF4 is likely also required for the generation of mature B cells. IRF8 promotes the early stages of the germinal center (GC) reaction whereas IRF4 is critical for later stages of GC reaction and the development of plasma cell. IRF4 and 8 show distinct expression pattern in B cell development. Expression of IRF4 is low in pro-B cells but its expression is significantly elevated in pre-B cells. The expression of IRF4 is moderate/low in naïve B cells but is induced significantly by BCR and CD40 signaling in GC B cells. The expression of IRF4 remains high in plasma cells. The expression of IRF8 remains stable throughout B cell development but its expression can be further induced by BCR signaling.

Figure 2. IRF4 and 8 limit pre-B cell expansion and promote light chain rearrangement

IRF4, whose expression is turned on by pre-BCR signaling, induces expression of Ikaros and Aiolos to suppress surrogate light chain (SLC) expression. Besides downregulating the pre-BCR, Ikaros and Aiolos also limit pre-B cell expansion by directly inhibiting the G1-S transition. In addition, IRF4 and 8 also promote light chain rearrangement and transcription, either through direct activation of Ig light chain enhancers or indirectly through attenuation of IL-7 signaling, the latter of which is achieved via a CXCL12 mediated chemotaxis which requires an IRF4-dependent induction of CXCR4 in pre-B cells. Expression of IRF8 is not induced by the pre-BCR; however, it is still possible that the activity of IRF8 can be modulated by pre-BCR signaling.

Fig. 3. IRF4 and 8 regulate the germinal center reaction and plasma cell development

IRF8 modulates the germinal center (GC) reaction by inducing the expression of Bcl-6 and activation-induced cytidine deaminase (AID) in centroblasts. IRF4, whose expression can only be detected in subsets of centrocytes, is critical for CSR and the downregulation of Bcl6 at the end stage of the GC reaction. Expression of IRF4 can be induced in GC B cells by signals emanating from the B cell receptor (BCR), CD40, and cytokines. It is proposed that a low level of IRF4 induces AID to promote CSR whereas a high level of IRF4 turns on Blimp-1 to favor plasma cell development. Blimp-1 is also found to induce IRF4. This autoregulatory loop between IRF4 and Blimp-1 is suggested to be necessary for overcoming Bcl-6 mediated repression of the Blimp-1 gene.