Irf8, also known as interferon regulatory factor 8, is a transcription factor of the IRF protein family. It is essential for myeloid cell lineage commitment and differentiation, and plays a role in the development and maturation of myeloid cells like dendritic cells, monocytes, macrophages. It is involved in pathways such as antigen processing and presentation, cytokine-related responses, and immune cell activation [2,4]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In cancer, Irf8-deleted mice show that TAM-specific Irf8 deletion prevents exhaustion of cancer-cell-reactive CTLs and suppresses tumor growth, indicating that IRF8-expressing TAMs promote CTL exhaustion in tumors [1]. Deletion of Irf8 in mice leads to massive accumulation of CD11b+Gr1+ immature myeloid cells, particularly PMN-MDSCs, and in human cancer patients, IRF8 is often silenced in MDSCs, which promote tumor immune evasion [2]. In microglia, constitutive and postnatal Irf8 deletion in mice leads to a loss of microglia identity, gain of DAM-like genes, reduced interaction of microglia with amyloidβ plaques, and lessening of neuronal loss [3].

In conclusion, Irf8 is crucial for normal immune cell development and function. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in cancer, immunodeficiency, and microglia-related disease conditions. These studies help in understanding the biological functions of Irf8 and provide insights into potential therapeutic strategies for related diseases.

References:

1. Nixon, Briana G, Kuo, Fengshen, Ji, LiangLiang, Hakimi, A Ari, Li, Ming O. 2022. Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer. In Immunity, 55, 2044-2058.e5. doi:10.1016/j.immuni.2022.10.002. https://pubmed.ncbi.nlm.nih.gov/36288724/

2. Moorman, Hannah R, Reategui, Yazmin, Poschel, Dakota B, Liu, Kebin. 2022. IRF8: Mechanism of Action and Health Implications. In Cells, 11, . doi:10.3390/cells11172630. https://pubmed.ncbi.nlm.nih.gov/36078039/

3. Saeki, Keita, Pan, Richard, Lee, Eunju, Kurotaki, Daisuke, Ozato, Keiko. 2024. IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs. In Nature immunology, 25, 1928-1942. doi:10.1038/s41590-024-01962-2. https://pubmed.ncbi.nlm.nih.gov/39313544/

4. Salem, Sandra, Salem, David, Gros, Philippe. 2020. Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases. In Human genetics, 139, 707-721. doi:10.1007/s00439-020-02154-2. https://pubmed.ncbi.nlm.nih.gov/32232558/