The IL15 gene encodes a pleiotropic four-α-helix bundle cytokine known as Interleukin-15 (IL-15), which is essential for the development, survival, and activation of immune cells, particularly Natural Killer (NK) cells and memory CD8+ T cells. Unlike many cytokines, IL-15 is primarily regulated at the post-transcriptional and translational levels rather than just transcriptionally, and it is uniquely delivered to target cells through trans-presentation, where it is shuttled to the cell surface bound to its high-affinity receptor, IL-15Rα ^[1]. The protein is widely expressed across a variety of tissues, including the placenta, skeletal muscle, kidney, lung, and heart, and is produced by both hematopoietic cells (such as monocytes, macrophages, and dendritic cells) and non-hematopoietic cells (such as epithelial cells and fibroblasts) ^[2]. Functionally, IL-15 triggers the JAK/STAT (specifically JAK1/3 and STAT3/5) and PI3K/AKT/mTOR signaling pathways to promote cellular proliferation and inhibit apoptosis by upregulating anti-apoptotic factors like BCL2 ^[3]. Because of its potent inflammatory effects, dysregulation of the IL15 gene is implicated in several pathologies: over-expression is strongly associated with autoimmune diseases like Celiac disease, Rheumatoid Arthritis, and Multiple Sclerosis, as well as certain malignancies like Adult T-cell Leukemia, while its deficiency can lead to severe immunodeficiency or impaired response to viral infections ^[4].

The B6-huIL15 mouse is a humanized model constructed through gene-editing technology, in which the region from partial intron 4 to TGA stop codon of mouse Il15 is replaced with the region from partial intron 4 to TGA stop codon of human IL15. This model can be used for research on autoimmune diseases like Celiac disease, Rheumatoid Arthritis, and Multiple Sclerosis, as well as certain malignancies like Adult T-cell Leukemia. Furthermore, it serves as a platform for the screening, development, and preclinical evaluation of IL15-targeted therapeutics.