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 is involved in various immune-related pathways such as antigen processing and presentation, cytokine-mediated activation, and immune cell development [2,5]. It also plays a role in hematopoiesis, bridging lymphoid and dendritic cell differentiation [3]. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, have been crucial in understanding its functions.

Deletion of Irf8 in mice leads to massive accumulation of CD11b+Gr1+ immature myeloid cells, particularly PMN-MDSCs [2]. In a murine breast cancer model, TAM-specific Irf8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth, indicating that Irf8 in tumor-associated macrophages (TAMs) promotes CTL exhaustion in cancer [1]. In 5xFAD model mice, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss, suggesting its importance in microglia-related functions [4].

In conclusion, Irf8 is a key transcription factor regulating both the immune and non-immune components in health and diseases. KO/CKO mouse models have revealed its role in cancer, microglia-related functions, and myeloid cell development, providing insights into the mechanisms of these biological processes and potential disease-related pathways.

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. Liang, Kai Ling, Laurenti, Elisa, Taghon, Tom. 2023. Circulating IRF8-expressing CD123+CD127+ lymphoid progenitors: key players in human hematopoiesis. In Trends in immunology, 44, 678-692. doi:10.1016/j.it.2023.07.004. https://pubmed.ncbi.nlm.nih.gov/37591714/

4. 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/

5. 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/