IRF4 explained

Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the IRF4 gene.[1] [2] [3] IRF4 functions as a key regulatory transcription factor in the development of human immune cells.[4] [5] The expression of IRF4 is essential for the differentiation of T lymphocytes and B lymphocytes as well as certain myeloid cells. 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.

The MUM1 symbol is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641).

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. IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription cofactors. 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 and dendritic cells.

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 and Th17 cells. IRF4 regulates this differentiation via apoptosis 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 and memory T cells. 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. IRF4 is necessary for effector function of T regulatory cells 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 to induce the expression of the Ikaros 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 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. IRF4 expression commences GC formation through its upregulation of transcription factors BCL6 and POU2AF1, which promote germinal center formation.[6] 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 and help preserve immunological memory to specific antigens.[7] 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. 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. 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.[8] IRF4 is a transcription factor that has been implicated in acute leukemia.[9] This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color.[10] A variant has been implicated in greying of hair.[11]

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.[12] 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[13] to a site near the IGH@ immunoglobulin heavy locus on the long (i.e. q) arm of chromosome 14 at position 32.33[14] [15]

Interactions

IRF4 has been shown to interact with:

See also

References

Further reading

Notes and References

  1. Grossman A, Mittrücker HW, Nicholl J, Suzuki A, Chung S, Antonio L, Suggs S, Sutherland GR, Siderovski DP, Mak TW . 6 . Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25 . Genomics . 37 . 2 . 229–233 . October 1996 . 8921401 . 10.1006/geno.1996.0547 . 42646350 . Grant Robert Sutherland .
  2. Xu D, Zhao L, Del Valle L, Miklossy J, Zhang L . Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes . Journal of Virology . 82 . 13 . 6251–6258 . July 2008 . 18417578 . 2447047 . 10.1128/JVI.00163-08 .
  3. Web site: Entrez Gene: IRF4 interferon regulatory factor 4.
  4. 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.
  5. 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
  6. 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.
  7. 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.
  8. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . 6 . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–676 . December 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
  9. Adamaki M, Lambrou GI, Athanasiadou A, Tzanoudaki M, Vlahopoulos S, Moschovi M . Implication of IRF4 aberrant gene expression in the acute leukemias of childhood . PLOS ONE . 8 . 8 . e72326 . 2013 . 23977280 . 3744475 . 10.1371/journal.pone.0072326 . free . 2013PLoSO...872326A .
  10. Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, Van Otterloo E, Kim RS, Bergsteinsdottir K, Ogmundsdottir MH, Magnusdottir E, Mishra PJ, Davis SR, Guo T, Zaidi MR, Helgason AS, Sigurdsson MI, Meltzer PS, Merlino G, Petit V, Larue L, Loftus SK, Adams DR, Sobhiafshar U, Emre NC, Pavan WJ, Cornell R, Smith AG, McCallion AS, Fisher DE, Stefansson K, Sturm RA, Steingrimsson E . 6 . A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway . Cell . 155 . 5 . 1022–1033 . November 2013 . 24267888 . 3873608 . 10.1016/j.cell.2013.10.022 .
  11. Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M, Chacón-Duque JC, Al-Saadi F, Johansson JA, Quinto-Sanchez M, Acuña-Alonzo V, Jaramillo C, Arias W, Barquera Lozano R, Macín Pérez G, Gómez-Valdés J, Villamil-Ramírez H, Hunemeier T, Ramallo V, Silva de Cerqueira CC, Hurtado M, Villegas V, Granja V, Gallo C, Poletti G, Schuler-Faccini L, Salzano FM, Bortolini MC, Canizales-Quinteros S, Rothhammer F, Bedoya G, Gonzalez-José R, Headon D, López-Otín C, Tobin DJ, Balding D, Ruiz-Linares A . 6 . A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features . Nature Communications . 7 . 10815 . March 2016 . 26926045 . 4773514 . 10.1038/ncomms10815 . 2016NatCo...710815A.
  12. Lynch RC, Gratzinger D, Advani RH . Clinical Impact of the 2016 Update to the WHO Lymphoma Classification . Current Treatment Options in Oncology . 18 . 7 . 45 . July 2017 . 28670664 . 10.1007/s11864-017-0483-z . 4415738 .
  13. Web site: IRF4 interferon regulatory factor 4 [Homo sapiens (Human)] - Gene - NCBI.
  14. Web site: IGH immunoglobulin heavy locus [Homo sapiens (Human)] - Gene - NCBI.
  15. Woessmann W, Quintanilla-Martinez L . Rare mature B-cell lymphomas in children and adolescents . Hematological Oncology . 37 . Suppl 1 . 53–61 . June 2019 . 31187530 . 10.1002/hon.2585 . free .
  16. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH . Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression . The Journal of Experimental Medicine . 195 . 8 . 1003–1012 . April 2002 . 11956291 . 2193700 . 10.1084/jem.20011128 .
  17. Brass AL, Zhu AQ, Singh H . Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers . The EMBO Journal . 18 . 4 . 977–991 . February 1999 . 10022840 . 1171190 . 10.1093/emboj/18.4.977 .
  18. Escalante CR, Shen L, Escalante MC, Brass AL, Edwards TA, Singh H, Aggarwal AK . Crystallization and characterization of PU.1/IRF-4/DNA ternary complex . Journal of Structural Biology . 139 . 1 . 55–59 . July 2002 . 12372320 . 10.1016/S1047-8477(02)00514-2 .
  19. Gupta S, Jiang M, Anthony A, Pernis AB . Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4 . The Journal of Experimental Medicine . 190 . 12 . 1837–1848 . December 1999 . 10601358 . 2195723 . 10.1084/jem.190.12.1837 .

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