Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the IRF4 gene.[5][6][7] IRF4 functions as a key regulatory transcription factor in the development of human immune cells.[8][9] The expression of IRF4 is essential for the differentiation of T lymphocytes and B lymphocytes as well as certain myeloid cells.[8] Dysregulation of the IRF4 gene can result in IRF4 functioning either as an oncogene or a tumor-suppressor, depending on the context of the modification.[8]
The MUM1 symbol is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641).
IRF4 is a transcription factor belonging to the Interferon Regulatory Factor (IRF) family of transcription factors.[8][9] In contrast to some other IRF family members, IRF4 expression is not initiated by interferons; rather, IRF4 expression is promoted by a variety of bioactive stimuli, including antigen receptor engagement, lipopolysaccharide (LPS), IL-4, and CD40.[8][9] IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription cofactors.[8][9] IRF4 frequently cooperates with the cofactors B-cell lymphoma 6 protein (BCL6) and nuclear factor of activated T-cells (NFATs).[8] IRF4 expression is limited to cells of the immune system, in particular T cells, B cells, macrophages and dendritic cells.[8][9]
IRF4 plays an important role in the regulation of T cell differentiation. In particular, IRF4 ensures the differentiation of CD4+ T helper cells into distinct subsets.[8] IRF4 is essential for the development of Th2 cells and Th17 cells. IRF4 regulates this differentiation via apoptosis and cytokine production, which can change depending on the stage of T cell development.[9] For example, IRF4 limits production of Th2-associated cytokines in naïve T cells while its upregulates the production of Th2 cytokines in effector and memory T cells.[8] While not essential, IRF4 is also believed to play a role in CD8+ cytotoxic T cell differentiation through its regulation of factors directly involved in this process, including BLIMP-1, BATF, T-bet, and RORγt.[8] IRF4 is necessary for effector function of T 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 alongside IRF8 to induce the expression of the Ikaros and Aiolos transcription factors, which decrease expression of the pre-B-cell-receptor.[9] IRF4 then regulates the secondary rearrangement of κ and λ chains, making IRF4 essential for the continued development of the BCR.[8]
IRF4 also occupies an essential position in the adaptive immune response of mature B cells. When IRF4 is absent, mature B cells fail to form germinal centers (GCs) and proliferate excessively in both the spleen and lymph nodes.[9] IRF4 expression commences GC formation through its upregulation of transcription factors BCL6 and POU2AF1, 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-affinity antibodies and help preserve immunological 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 upregulates Blimp-1 and Zbtb20 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 for isotype 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 the AID enzyme, a component necessary for inducing mutations in immunoglobulin switch regions of B cell DNA during somatic 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]
Among myeloid cells, IRF4 expression has been identified in dendritic cells (DCs) and macrophages.[8][9]
The transcription factors IRF4 and IRF8 work in concert to achieve DC differentiation.[8][9] IRF4 expression is responsible for inducing development of CD4+ DCs, while IRF8 expression is necessary for the development of CD8+ 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 factor GM-CSF.[8] IRF4 expression is necessary for ensuring that monocyte-derived dendritic cells (Mo-DCs) can cross-present antigen to CD8+ cells.[8]
IRF4 and IRF8 are also significant transcription factors in the differentiation of common 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 of M2 macrophages.[8] JMJD3, which regulates IRF4, has been identified as an important regulator of M2 macrophage polarization, suggesting that IRF4 may also take part in this regulatory process.[8]
In melanocytic cells the IRF4 gene may be regulated by MITF.[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]
The World Health Organization (2016) provisionally defined large B-cell lymphoma with IRF4 rearrangement as a rare indolent large B-cell lymphoma of children and adolescents. This indolent lymphoma mimics, and must be distinguished from, pediatric-type follicular lymphoma.[16] The hallmark of large B-cell lymphoma with IRF4 rearrangement is the overexpression of the IRF4 gene by the disease's malignant cells. This overexpression is forced by the acquisition in these cells of a translocation of IRF4 from its site on the short (i.e. p) arm of chromosome 6 at position 25.3[17] to a site near the IGH@ immunoglobulin heavy locus on the long (i.e. q) arm of chromosome 14 at position 32.33[18][19]
IRF4 has been shown to interact with: