Mouse models have been essential to advancing biomedical research because they share many physiological and anatomical trains with humans and can be manipulated at a genomic or cellular level to study basic biology or diseases. Immunology research has benefited greatly from mouse models, and mice that are modified to have components of the humanized immune system (HIS) are especially useful.
Starting in the 2000s, an array of different HIS models were developed. These models use immunodeficient mice, which are also used for tumor or tissue xenograft experiments as they do not readily reject non-self tissue. The first models were developed using immunodeficient NOD/SCID or RAG1/2null mice that had mutations introduced into the IL2rα gene, which were backcrossed to make NOD/SCID/γcnull  or Rag1/2nullγcnull  mice. These mice lack B, T, and natural killer (NK) cells and have fewer dendritic cells and macrophages. Engraftment of these immunodeficient strains with human hematopoietic stem cells (HSCs) allows for differentiation and expansion of human immune system cells. Numerous studies have contributed to optimizing HIS mouse models, including evaluating different methods of immune system ablation, age of mice, and delivery route and sources of CD34+ HSCs. Improved HIS models support the differentiation of various immune cell subsets, demonstrates tolerance of human cells, and can be preconditioned by pharmacological or radiological methods to open the bone marrow niche.
The study of human NK cells has been advanced in HIS models that have been optimized for their differentiation and development. NK cells are part of the innate immune system and are involved in immunosurveillance for the detection of viruses or tumor cells. NK cells detect and respond to these threats through engagement of activating and inhibitory receptors. Recent studies have defined different subsets of NK cells based on expression of these receptors as well as other phenotypic markers, especially CD16 and CD56, and these subsets may be derived from common progenitors and have different effector functions like cytokine secretion and cytotoxicity. Many tumor-associated NK cells show high expression of CD56, although phenotypes vary widely in terms of activating and inhibitory receptor expression and effector functions, due in part to the effects of the immunosuppressive tumor microenvironment.
The development of HIS mice that express a full complement of human NK cells has taken time due to the requirement of IL-15 for acquisition of effector functions. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice have become a model of choice for human NK cell studies, and pre-activation of HSC with IL-15 in vitro or treatment of mice with the innate immune ligand poly I:C dramatically improved effector functions of NK cell subsets in HIS mice4. More recently, NSG mice have been engineered to express human IL-15 as well as human IL-7, which has further improved the functionality of NK cell subsets. NK cell-optimized HIS mice can be engrafted with tumor cell lines or patient derived xenografts, and anti-tumor responses by NK cell subsets can be evaluated in the presence of experimental therapies that aim to enhance this immune response.
NK cells are a sought-after target of experimental immunotherapies because of their ability to target tumor cells rapidly and effectively. HIS mice with a fully functional complement of human NK cells are an essential tool for these studies and provide a necessary bridge between basic and clinical research.
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