Interferon regulatory factor 4 (IRF4) also known as ''MUM1'' is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''IRF4''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, located at 6p25-p23. IRF4 functions as a key regulatory

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

in the development of human immune cells.Nam S, Lim J-S (2016). "Essential role of interferon regulatory factor 4 (IRF4) in immune cell development." ''Arch. Pharm. Res''. 39: 1548–1555
doi:10.1007/s12272-016-0854-1
Shaffer AL, Tolga Emre NC, Romesser PB, Staudt LM (2009). "IRF4: Immunity. Malignancy! Therapy?" ''Clinical Cancer Research''. 15 (9): 2954-2961
doi:10.1158/1078-0432.CCR-08-1845
/ref> The expression of IRF4 is essential for the differentiation of

T lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

and

B lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

as well as certain

myeloid cells A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases). Structure When stained with the usual dyes, the cytoplasm is distinctly basophilic ...

. The ''MUM1'' symbol is

polysemous Polysemy ( or ; ) is the capacity for a sign (e.g. a symbol, a morpheme, a word, or a phrase) to have multiple related meanings. For example, a word can have several word senses. Polysemy is distinct from ''monosemy'', where a word has a single ...

; although it is an older synonym for ''IRF4'' (HGNC:6119), it is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641; located at 19p13.3). Dysregulation of the ''IRF4'' gene can result in ''IRF4'' functioning either as an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

or a tumor-suppressor, depending on the context of the modification.

Immune cell development

IRF4 is a transcription factor belonging to the Interferon Regulatory Factor (IRF) family of transcription factors. 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 Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T helper cell, TH cells to CD40 activates antigen presenting cells and induces a ...

. IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription

cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...

. IRF4 frequently cooperates with the cofactors B-cell lymphoma 6 protein (BCL6) and nuclear factor of activated T-cells (NFATs). IRF4 expression is limited to cells of the immune system, in particular T cells, B cells,

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

T cell differentiation

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. IRF4 is essential for the development of

Th2 cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

and Th17 cells. IRF4 regulates this differentiation via

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and cytokine production, which can change depending on the stage of T cell development. For example, IRF4 limits production of Th2-associated cytokines in naïve T cells while its upregulates the production of Th2 cytokines in

effector Effector may refer to: *Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein * ''Effector'' (album), a music album by the Experimental Techno group Download * ''EFFector'', a publication of the El ...

and

memory T cells Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

. 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 PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene ''PRDM1'' located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and p ...

, BATF, T-bet, and RORγt. IRF4 is necessary for effector function of

T regulatory cells T, or t, is the twentieth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is der ...

due to its role as a regulatory factor for Blimp-1.

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 Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the ''IRF8'' gene. IRF8 is a transcription factor that plays critical roles in the regulation of l ...

to induce the expression of the

Ikaros IKAROS (Interplanetary Kite-craft Accelerated by Radiation Of the Sun) is a Japan Aerospace Exploration Agency (JAXA) experimental spacecraft. The spacecraft was launched on 20 May 2010, aboard an H-IIA rocket, together with the ''Akatsuki'' (V ...

and Aiolos transcription factors, which decrease expression of the pre-B-cell-receptor. IRF4 then regulates the secondary rearrangement of κ and λ chains, making IRF4 essential for the continued development of the BCR. IRF4 also occupies an essential position in the

adaptive immune response The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...

of mature B cells. When IRF4 is absent, mature B cells fail to form germinal centers (GCs) and proliferate excessively in both the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

and

lymph nodes A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

. IRF4 expression commences GC formation through its upregulation of transcription factors BCL6 and

POU2AF1 POU domain class 2-associating factor 1 is a protein that in humans is encoded by the ''POU2AF1'' gene. The protein is also termed Oct coactivator from B cells (i.e. OCAB), Oct binding factor 1 (OBF1 or OBF-1), and, as commonly found in the liter ...

, which promote germinal center formation.Laidlaw BJ, Cyster JG (2021). "Transcriptional regulation of memory B cell differentiation." ''Nat. Rev. Immunol''. 21: 209–220
doi:10.1038/s41577-020-00446-2
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.

Long-lived plasma cells

Long-lived plasma cells are memory B cells that secrete high-affinity

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

and help preserve

immunological memory Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally, these are secondary, tertiary and other subs ...

to specific antigens.Khodadadi 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
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. A limited presence of IRF4 activates BCL6, which is essential for the formation of germinal centers, from which plasma cells differentiate. In contrast, elevated expression of IRF4 represses BCL6 expression and upregulates Blimp-1 and Zbtb20 expression. This response, dependent on a high dose of IRF4, helps initiate the differentiation of germinal center B cells into plasma cells. 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. 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 Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes), as seen during class switching. A major component of the process of affinity maturation, SHM div ...

. In the absence of IRF4, B cells will not differentiate into Ig-secreting plasma cells. 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.

Myeloid cell differentiation

Among myeloid cells, IRF4 expression has been identified in dendritic cells (DCs) and macrophages.

Dendritic cells (DCs)

The transcription factors IRF4 and IRF8 work in concert to achieve DC differentiation. IRF4 expression is responsible for inducing development of CD4+ DCs, while IRF8 expression is necessary for the development of CD8+ DCs. Expression of either IRF4 or IRF8 can result in CD4-/CD8- DCs. Differentiation of DC subtypes also depends on IRF4's interaction with the growth factor

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

. IRF4 expression is necessary for ensuring that monocyte-derived dendritic cells (Mo-DCs) can cross-present antigen to CD8+ cells.

Macrophages

IRF4 and IRF8 are also significant transcription factors in the differentiation of common myeloid progenitors (CMPs) into macrophages. 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. 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.

Clinical significance

In melanocytic cells the IRF4 gene may be regulated by

MITF Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription factor ...

. IRF4 is a transcription factor that has been implicated in acute leukemia. This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. A variant has been implicated in greying of hair. * The World Health Organization (2016) provisionally defined large B-cell lymphoma with IRF4 rearrangement as a rare indolent

large B-cell lymphoma The large-cell lymphomas have large cells. One classification system for lymphomas divides the diseases according to the size of the white blood cells that have turned cancerous. A large cell, in this context, has a diameter of 17 to 20 μm. ...

of children and adolescents. This indolent lymphoma mimics, and must be distinguished from,

pediatric-type follicular lymphoma Pediatric-type follicular lymphoma (PTFL) is a disease in which malignant B-cells (i.e. a lymphocyte subtype originating from the bone marrow) accumulate in, overcrowd, and cause the expansion of the lymphoid follicles in, and thereby enlargement ...

. 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 to a site near the IGH@ immunoglobulin heavy locus on the long (i.e. q) arm of chromosome 14 at position 32.33

Interactions

IRF4 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: * Aiolos, * BATF3, *

, * BCL6, *

, *

, * IL-4, *

, *

, * JMJD3, * MMP12, *

NFATC2 Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the ''NFATC2'' gene. Function This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-bindin ...

, *

SPI1 Transcription factor PU.1 is a protein that in humans is encoded by the ''SPI1'' gene. Function This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development. The nuclear pro ...

, and *

STAT6 Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor com ...

References

External links

* * {{JAK-STAT signaling pathway Transcription factors