Irf4, also known as MUM1, is a transcription factor in the interferon regulatory factor (IRF) family. It is a key regulator of immune cell development and function, mediating critical immune responses via interactions with upstream signaling pathways like the T-cell receptor and B-cell receptor pathways [2]. It is essential for the development and function of immune cells such as T and B cells, macrophages, and DC [4].

Deleting Arid1a in activated murine B cells disrupts Irf4-dependent transcriptional networks and blocks plasma cell differentiation, indicating that Arid1a is required for Irf4 expression and functionally associates with Irf4 protein on chromatin, which is crucial for establishing plasma cell identity in multiple myeloma [1]. A knock-in mouse model of heterozygous T95R (a mutation in Irf4) showed a severe defect in antibody production, as patients with this mutation have impaired B cell maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, along with reduced TH17 and TFH populations and decreased cytokine production in T cells [3]. During chronic infection in mice, reducing Irf4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development, as high amounts of Irf4 drive T cell exhaustion [5].

In conclusion, Irf4 is vital for immune cell development, function, and plasma cell differentiation. Gene-targeted mouse models, such as those with Arid1a deletion, Irf4 knock-in with specific mutations, and Irf4 reduction during chronic infection, have revealed its role in multiple myeloma, immunodeficiency, and T cell exhaustion. These findings contribute to understanding the mechanisms underlying these disease conditions and may provide potential therapeutic strategies.

References:

1. Bolomsky, Arnold, Ceribelli, Michele, Scheich, Sebastian, Muppidi, Jagan, Young, Ryan M. 2024. IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma. In Cancer cell, 42, 1185-1201.e14. doi:10.1016/j.ccell.2024.05.026. https://pubmed.ncbi.nlm.nih.gov/38906156/

2. Wong, Regina Wan Ju, Ong, Jolynn Zu Lin, Theardy, Madelaine Skolastika, Sanda, Takaomi. 2022. IRF4 as an Oncogenic Master Transcription Factor. In Cancers, 14, . doi:10.3390/cancers14174314. https://pubmed.ncbi.nlm.nih.gov/36077849/

3. Fornes, Oriol, Jia, Alicia, Kuehn, Hye Sun, Turvey, Stuart E, Wang, Ji-Yang. 2023. A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. In Science immunology, 8, eade7953. doi:10.1126/sciimmunol.ade7953. https://pubmed.ncbi.nlm.nih.gov/36662884/

4. Xiao, Ze Xiu, Liang, Rongzhen, Olsen, Nancy, Zheng, Song Guo. 2024. Roles of IRF4 in various immune cells in systemic lupus erythematosus. In International immunopharmacology, 133, 112077. doi:10.1016/j.intimp.2024.112077. https://pubmed.ncbi.nlm.nih.gov/38615379/

5. Man, Kevin, Gabriel, Sarah S, Liao, Yang, Shi, Wei, Kallies, Axel. 2017. Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. In Immunity, 47, 1129-1141.e5. doi:10.1016/j.immuni.2017.11.021. https://pubmed.ncbi.nlm.nih.gov/29246443/