NKG mice are a type of severe immunodeficient mouse developed by Cyagen by deleting the Il2rg gene from the NOD-Scid strain. This strain lacks mature T, B, and NK cells, exhibits reduced complement activity, and weak macrophage phagocytosis of human cells. As a result, NKG mice can efficiently engraft human hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), patient-derived xenografts (PDX), or adult stem cells and tissues.

In immunology research, direct studies on mice may not fully represent the human immune system due to physiological and immune system differences. However, by transplanting human peripheral blood mononuclear cells (PBMCs) or hematopoietic stem cells (HSCs) into immunodeficient mice, we can partially or completely replace the mouse immune system with a human counterpart. This approach enables in vivo simulation of human immune system function, providing an effective model for studying human immunity. However, in actual human-mouse xenotransplantation, due to the lack of specific human cytokines and supportive stromal cells in mice, transplantation using conventional immunodeficient mice is likely to result in variations in immune reconstitution efficiency. Modifying immunodeficient mice via gene editing technology to establish a humanized immune microenvironment in mice and promote the functional maturation of human-derived cells is a universal strategy for improving the efficiency of immune reconstitution in xenotransplantation.

The IL2 gene encodes Interleukin-2, a crucial cytokine primarily secreted by activated CD4+ and CD8+ T lymphocytes, and to a lesser extent, by natural killer (NK) cells. This protein, also known as T-cell growth factor, plays a pivotal role in regulating immune responses by promoting the growth, proliferation, and differentiation of various "disease-fighting blood cells", including T cells, B cells, NK cells, monocytes, macrophages, and oligodendrocytes ^[1]. IL2 expression is tightly regulated; it is upregulated upon T-cell activation through T-cell receptor signaling and can be inhibited by factors like TOB and TGF-beta ^[2]. The encoded IL-2 protein mediates its effects by binding to the IL-2 receptor (IL-2R), a complex found on lymphocytes, which then activates downstream signaling pathways such as JAK-STAT, PI3K/Akt/mTOR, and MAPK/ERK, influencing T-cell survival, differentiation, and the maintenance of immune tolerance by supporting regulatory T cells (Tregs) while inhibiting pro-inflammatory Th17 cell differentiation ^[3]. Deregulation of IL2 function, whether due to deficiency or excess, is implicated in various autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, Sjögren's syndrome, and multiple sclerosis, as well as certain cancers like metastatic melanoma, renal cell carcinoma, and non-Hodgkin lymphoma ^[4].

NKG-Rosa26-CAG-hIL2 mouse is a model constructed via gene editing technology, in which the CAG promoter-Human IL2 cDNA-rBG pA cassette is cloned into intron 1 of ROSA26. Compared to NKG mice, NKG-Rosa26-CAG-hIL2 mice support the engraftment and reconstitution of human T cells after transplantation with human cells (such as PBMC or HSC), optimizing the outcome of immune reconstitution. This model provides an excellent experimental platform for human immune system reconstitution, cell or tissue transplantation, and the screening of anti-tumor drugs.