Interferon regulatory factor 4 (IRF4) also known as MUM1 is aprotein that in humans is encoded by theIRF4gene.[5][6][7] IRF4 functions as a key regulatorytranscription factor in the development of human immune cells.[8][9] The expression of IRF4 is essential for the differentiation ofT lymphocytes andB lymphocytes as well as certainmyeloid cells.[8] Dysregulation of theIRF4 gene can result inIRF4 functioning either as anoncogene or atumor-suppressor, depending on the context of the modification.[8]
TheMUM1 symbol is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641).
IRF4 plays an important role in the regulation of T cell differentiation. In particular, IRF4 ensures the differentiation ofCD4+ T helper cells into distinct subsets.[8] IRF4 is essential for the development ofTh2 cells andTh17 cells. IRF4 regulates this differentiation viaapoptosis andcytokine production, which can change depending on the stage of T cell development.[9] For example, IRF4 limits production of Th2-associated cytokines innaïve T cells while its upregulates the production of Th2 cytokines ineffector andmemory T cells.[8] While not essential, IRF4 is also believed to play a role inCD8+ cytotoxic T cell differentiation through its regulation of factors directly involved in this process, includingBLIMP-1,BATF,T-bet, andRORγt.[8] IRF4 is necessary for effector function ofT regulatory cells due to its role as a regulatory factor for BLIMP-1.[8]
IRF4 is an essential regulatory component at various stages of B cell development. In early B cell development, IRF4 functions alongsideIRF8 to induce the expression of theIkaros andAiolos transcription factors, which decrease expression of the pre-B-cell-receptor.[9] IRF4 then regulates the secondary rearrangement ofκ and λ chains, making IRF4 essential for the continued development of theBCR.[8]
IRF4 also occupies an essential position in theadaptive immune response of mature B cells. When IRF4 is absent, mature B cells fail to formgerminal centers (GCs) and proliferate excessively in both thespleen andlymph nodes.[9] IRF4 expression commences GC formation through its upregulation of transcription factors BCL6 andPOU2AF1, which promote germinal center formation.[10] IRF4 expression decreases in B cells once the germinal center forms, since IRF4 expression is not necessary for sustained GC function; however, IRF4 expression increases significantly when B cells prepare to leave the germinal center to form plasma cells.[9]
Long-lived plasma cells are memory B cells that secrete high-affinityantibodies and help preserveimmunological memory to specific antigens.[11] IRF4 plays a significant role at multiple stages of long-lived plasma cell differentiation. The effects of IRF4 expression are heavily dependent on the quantity of IRF4 present.[10] A limited presence of IRF4 activates BCL6, which is essential for the formation of germinal centers, from which plasma cells differentiate.[11] In contrast, elevated expression of IRF4 represses BCL6 expression and upregulatesBLIMP-1 andZbtb20 expression.[11] This response, dependent on a high dose of IRF4, helps initiate the differentiation of germinal center B cells into plasma cells.[11]
IRF4 expression is necessary forisotype class switch recombination in germinal center B cells that will become plasma cells. B cells that lack IRF4 fail to undergo immunoglobulin class switching.[9] Without IRF4, B cells fail to upregulate theAID enzyme, a component necessary for inducing mutations inimmunoglobulin switch regions of B cell DNA duringsomatic hypermutation.[9] In the absence of IRF4, B cells will not differentiate into Ig-secreting plasma cells.[9]
IRF4 expression continues to be necessary for long-lived plasma cells once differentiation has occurred. In the absence of IRF4, long-lived plasma cells disappear, suggesting that IRF4 plays a role in regulating molecules essential for the continued survival of these cells.[11]
The transcription factors IRF4 and IRF8 work in concert to achieve DC differentiation.[8][9] IRF4 expression is responsible for inducing development ofCD4+ DCs, while IRF8 expression is necessary for the development ofCD8+ DCs.[9] Expression of either IRF4 or IRF8 can result in CD4-/CD8- DCs.[9] Differentiation of DC subtypes also depends on IRF4's interaction with the growth factorGM-CSF.[8] IRF4 expression is necessary for ensuring thatmonocyte-derived dendritic cells (Mo-DCs) can cross-present antigen to CD8+ cells.[8]
IRF4 and IRF8 are also significant transcription factors in the differentiation ofcommon myeloid progenitors (CMPs) into macrophages.[8] IRF4 is expressed at a lower level than IRF8 in these progenitor cells; however, IRF4 expression appears to be particularly important for the development ofM2 macrophages.[8]JMJD3, which regulates IRF4, has been identified as an important regulator ofM2 macrophage polarization, suggesting that IRF4 may also take part in this regulatory process.[8]
In melanocytic cells theIRF4 gene may be regulated byMITF.[12] IRF4 is a transcription factor that has been implicated in acute leukemia.[13] This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color.[14] A variant has been implicated in greying of hair.[15]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Grossman A, Mittrücker HW, Nicholl J, Suzuki A, Chung S, Antonio L, et al. (October 1996). "Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25".Genomics.37 (2):229–233.doi:10.1006/geno.1996.0547.PMID8921401.S2CID42646350.
^abLaidlaw BJ, Cyster JG (2021). "Transcriptional regulation of memory B cell differentiation."Nat. Rev. Immunol.21: 209–220.doi:10.1038/s41577-020-00446-2.
^abcdefKhodadadi L, Cheng Q, Radbruch A and Hiepe F (2019). "The Maintenance of Memory Plasma Cells."Front. Immunol.10: 721.doi:10.3389/fimmu.2019.00721.
^Lynch RC, Gratzinger D, Advani RH (July 2017). "Clinical Impact of the 2016 Update to the WHO Lymphoma Classification".Current Treatment Options in Oncology.18 (7) 45.doi:10.1007/s11864-017-0483-z.PMID28670664.S2CID4415738.
Mamane Y, Sharma S, Grandvaux N, Hernandez E, Hiscott J (January 2002). "IRF-4 activities in HTLV-I-induced T cell leukemogenesis".Journal of Interferon & Cytokine Research.22 (1):135–143.doi:10.1089/107999002753452746.PMID11846984.
