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 requirement for IRF4 and 8 throughout B cell development. This review focuses on the recent advances on roles of IRF4 and 8 in B cell development. Introduction The interferon regulatory factor family of transcription factor (IRF) consists of nine mammalian members that are important regulators of both immunity and other physiological processes [1]. Two members of this family IRF4 (also known as Pip LSIRF LCSAT and MUM1) and IRF8 (also known as ICSBP) are unique in that Stattic they are highly homologous to each other rather than to other IRF family members and they are expressed exclusively in the immune system. IRF4 and 8 interact with other transcription factors to either stimulate or repress gene expression in the immune system. The best characterized interacting partners of IRF4 and 8 are the Ets transcription factor family members PU.1 and Spi-B. It has been shown that IRF4 and 8 dimerize with PU.1 or Spi-B and bind to the Ets-IRF composite element (EICE; GGAAnnGAAA) located in immunoglobulin (Ig) light chain κ 3’ (Ek3’) and λ gene enhancer regions [2-4]. {More recently another IRF-Ets composite sequence IECS; has also been identified on the target genes of IRF8[5]. The presence of EICE or IECS sites on many putative targets of IRF4 and 8 suggests that interactions of IRF4 and 8 with PU.1 and Spi-B are likely to be common regulatory mechanisms in the immune system. In addition IRF4 and 8 have also been found to interact with the other key transcription Stattic factors E2A NFAT and as well as other members of the IRF family [6-8]. The roles of IRF4 and 8 in immune Stattic system development and function have been well-documented. For example IRF4 is critical for Th2 and Th17 cell development whereas IRF4 and IRF8 together are essential for macrophage and dendritic cell (DC) development and function [9-12]. Recently a series of studies have established an additional role for IRF4 and 8 as essential regulators of B cell development in which they have been shown to be critical for pre-B cell development receptor editing germinal center (GC) reaction and plasma cell differentiation (Figure Rabbit polyclonal to ZNF223. 1)[13-21]. Figure 1 IRF4 and 8 are required throughout B cell development IRF4 and 8 function redundantly to control pre-B cell development The identification of IRF4 and 8 as the transcription factors that bind to Stattic an EICE motif located in the immunoglobulin Ek3’ and λ gene enhancer regions provided the early evidence that IRF4 and 8 might play an overlapping role in pre-B cell development[3 4 Indeed B cell development is almost completely blocked at the large pre-B cell stage in IRF4 and 8 compound mutant mice (IRF4 8 Moreover IRF4 and IRF8 were found to be sufficient individually to rescue the development of IRF4 8 pre-B cells confirming that they function redundantly in pre-B cell development[15]. Interestingly IRF4 8 pre-B cells are hyperproliferative suggesting that IRF4 and 8 negatively regulate pre-B cell proliferation. Indeed recent findings from both ourselves and others have demonstrated that IRF4 and 8 are critical not only for light chain rearrangement but also for limiting pre-B cell expansion (Figure 2)[15 17 20 22 Figure 2 IRF4 and 8 limit pre-B cell expansion and promote light chain rearrangement IRF4 and 8 orchestrate the transition from cycling pre-B to small resting pre-B by inducing the expression of Ikaros and Aiolos Pre-B cells consist of two subsets: large pre-B and small pre-B (see Box 1). Recent studies have demonstrated that IRF4 and 8 orchestrate the transition from large pre-B to small pre-B by inducing the expression of the Ikaros family transcription factors Ikaros and Aiolos[17]. Ikaros and Aiolos have been shown to downregulate the pre-B cell receptor (BCR) by suppressing the expression of the surrogate light chain (SLC) ([23 24 Expression of Ikaros and Aiolos is known to be elevated in pre-B cells and at least expression of Aiolos has been shown to be induced by pre-BCR signaling[23 25 Interestingly the expression of Ikaros and Aiolos is induced by IRF4 and 8 in pre-B cells and expression of IRF4 itself is also induced by pre-BCR signaling[23]. Thus pre-BCR signaling induces the expression of IRF4 which in turn stimulates the expression of Ikaros and Aiolos (Figure 2)..