Interferon regulatory factor 4 (IRF4) also known as MUM1 is a
protein that in humans is encoded by the IRF4gene.[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 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]
B cell differentiation
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
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]
Myeloid cell differentiation
Among myeloid cells, IRF4 expression has been identified in dendritic cells (DCs) and macrophages.[8][9]
Dendritic cells (DCs)
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]
Macrophages
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]
Clinical significance
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]
^"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.
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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.
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abcdefKhodadadi L, Cheng Q, Radbruch A and Hiepe F (2019). "The Maintenance of Memory Plasma Cells." Front. Immunol. 10: 721.
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^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.
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