SLFN2, also known as Schlafen 2, is a cytoplasmic protein involved in multiple biological processes. It plays a crucial role in T cell-mediated immunity, type I interferon responses, and the regulation of cell quiescence in T cells, monocytes, and hematopoietic stem cells. It is associated with pathways such as the NF-κB pathway, and is important for maintaining normal cell functions and immune responses. Genetic mouse models have been valuable for studying its functions [1-4].

In T cell-specific Slfn2-deficient mice, there is an accumulation of tRNA fragments due to the failure of Slfn2 to protect tRNAs from stress-induced cleavage. This leads to translation repression, inhibited up-regulation of IL-2Rβ and IL-2Rγ, and ultimately renders T cells insensitive to interleukin-2's mitogenic effects, highlighting its importance in T cell-mediated immunity [1]. In Slfn2-mutant mice (elektra), T cells and monocytes show a loss of quiescence. These cells have disrupted cholesterol and lipid homeostasis, elevated de novo sterol synthesis, and an increased proportion of T cells ready to replicate DNA. They are also more susceptible to infection, with reduced numbers of T cells and monocytes that fail to proliferate and instead undergo apoptosis. This reveals Slfn2's role in maintaining immune cell quiescence and defense against pathogens [2,3]. Additionally, in the context of T-cell acute lymphoblastic leukemia (T-ALL), targeting Slfn2 to disrupt T-cell quiescence can prevent the development and progression of the disease [4].

In conclusion, Slfn2 is essential for maintaining cell quiescence in various immune cells, protecting tRNAs in T cells to enable proper immune responses, and modulating type I interferon responses through the NF-κB pathway. The study of Slfn2 using gene knockout (KO) mouse models, such as the elektra mouse, has provided valuable insights into its role in T-cell-mediated immunity and diseases like T-ALL, offering potential therapeutic strategies for malignancies [1-4].

References:

1. Yue, Tao, Zhan, Xiaoming, Zhang, Duanwu, Moresco, Eva Marie Y, Beutler, Bruce. . SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity. In Science (New York, N.Y.), 372, . doi:10.1126/science.aba4220. https://pubmed.ncbi.nlm.nih.gov/33986151/

2. Omar, Ibrahim, Rom, Oren, Aviram, Michael, Parks, John S, Berger, Michael. 2017. Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis. In Immunology, 152, 484-493. doi:10.1111/imm.12785. https://pubmed.ncbi.nlm.nih.gov/28672048/

3. Berger, Michael, Krebs, Philippe, Crozat, Karine, Akira, Shizuo, Beutler, Bruce. 2010. An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. In Nature immunology, 11, 335-43. doi:10.1038/ni.1847. https://pubmed.ncbi.nlm.nih.gov/20190759/

4. Goldshtein, Aviya, Zerbib, Shani Mistriel, Omar, Ibrahim, Popkin, Daniel, Berger, Michael. . Loss of T-cell quiescence by targeting Slfn2 prevents the development and progression of T-ALL. In Oncotarget, 7, 46835-46847. doi:10.18632/oncotarget.9390. https://pubmed.ncbi.nlm.nih.gov/27206675/