An Introduction to Common Immunodeficient Mouse Models

Updated on 2026/10/28

Immunodeficient mice have defects in one or more components of the immune system, such as T cells, B cells or natural killer (NK) cells. Their reduced ability to reject foreign tissue allows selected strains to support the engraftment of human cells and tumors, as well as the development of humanized immune system models ^[1-2].

These models are widely used in:

• Oncology: tumor growth, metastasis and anti-tumor drug screening
• Immunology: immune cell development, proliferation and disease mechanisms
• Infectious disease: host–pathogen interactions, including studies requiring human immune cells or tissues
• Stem cell biology: transplantation and differentiation of human stem cells

This guide first compares the main strains side by side, then traces the development of widely used immunodeficient mice from nude mice to NKG mice, and explains how to choose a host for CAR-T, PDX and humanized immune system studies. The best choice depends on the transplanted cells or tissues, experimental endpoints, conditioning strategy, and required study duration.

Nude vs. SCID vs. NOD-SCID vs. NKG Mice: At a Glance

The table below summarizes how the four main strains differ; each is described in more detail in the next section. Greater immunodeficiency can improve the engraftment of human cells, but it does not automatically make a model more suitable for every experiment: host selection should also account for the tumor or cell type, treatment mechanism and required study duration.

The Evolution and Types of Immunodeficient Mice

Successive immunodeficient mouse models have reduced different immune barriers to human cell engraftment. Major milestones include T cell-deficient nude mice in the 1960s, SCID mice in 1983, NOD-SCID mice in the 1990s, and strains with disrupted Il2rg signaling, including NOG, NSG and NKG mice ^[2-3].

Figure 1. The evolution of immunodeficient mice for human immune system models ^[4].

Nude mice (1960s): an early immunodeficient model

Nude mice, named for their hairless appearance, were first described in the 1960s and shown to lack a thymus in 1968. In 1969, they were reported to accept a human tumor xenograft, establishing them as an early host for human cancer studies ^{[3, 5]}.

Nude mice carry a spontaneous loss-of-function mutation in the Foxn1 gene, which disrupts the development of hair follicles and the thymic epithelium ^[2-3]. The result is athymia and a marked deficiency of mature T cells, impairing T cell-mediated immunity and T helper cell-dependent antibody responses. Nude mice have impaired T cell-mediated graft rejection and remain a common, cost-effective host for many human tumor cell line xenografts.

Their limitations:

• They retain B cells and functional NK cells. Residual innate immunity can limit the engraftment of some human tumors and other human cells ^[2–5].
• Small populations of extrathymically derived T cells can accumulate with age, a phenomenon often described as “T cell leakiness” ^[5]. This differs from the leakiness seen in SCID mice (see below): in nude mice, the leaky T cells develop outside the absent thymus, whereas in SCID mice, functional T and B cells arise when occasional V(D)J recombination events succeed despite the Prkdc^scid defect.

SCID mice (1983): deficient in mature T and B cells

Severe combined immunodeficiency (SCID) mice were described in 1983 in the C.B-17 strain. The Prkdc^scid mutation impairs V(D)J recombination, preventing normal T and B cell maturation. However, some C.B-17-scid mice become “leaky” with age and produce functional T or B cells. Their NK cell activity remains robust ^[2-3].

The Prkdc^scid mutation also impairs DNA double-strand break repair. Strains carrying this mutation are sensitive to irradiation and certain DNA-damaging agents, so conditioning and treatment regimens require strain-specific optimization. For studies involving irradiation-based conditioning or DNA-damaging therapies, the radiosensitivity of Prkdc^scid-based hosts should be considered during model selection and experimental design.

NOD-SCID mice (1990s): adding innate immune defects

The non-obese diabetic (NOD) strain, reported in 1980, spontaneously develops immune cell infiltration of the pancreatic islets (insulitis), followed by destruction of insulin-producing β cells and autoimmune diabetes. It also carries multiple innate immune abnormalities, including complement component C5 deficiency and functional defects affecting NK cells, macrophages and dendritic cells ^[2-3].

NOD-SCID mice, first reported in 1992, were generated by transferring the Prkdc^scid mutation from C.B-17-scid mice onto the NOD background ^[7].

NOD-SCID mice ^[7]:

• Do not spontaneously develop the autoimmune diabetes characteristic of immunocompetent NOD mice
• Lack functional mature T and B cells
• Retain the innate immune defects of the NOD background
• Show much lower leakiness than C.B-17-scid mice

These features established NOD-SCID mice as important recipients for human hematopoietic cells and tumors. Their main limitations are residual NK cell activity and a high incidence of spontaneous thymic lymphomas. A mean lifespan of approximately 8.5 months was reported for NOD/LtSz-scid mice under specific pathogen-free conditions ^[7].

NKG mice: deficient in mature T, B and functional NK cells

A major advance came from disrupting signaling through the IL-2 receptor common gamma chain gene, Il2rg, on the NOD-scid background, as reported for NOG mice in 2002 and NSG mice in 2005 ^{[3, 6]}. NKG mice belong to this broader group of severely immunodeficient hosts. Cyagen developed NKG mice by deleting Il2rg on the NOD-scid background.

Loss of functional common gamma chain signaling affects the cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 ^[2]. In particular, impaired IL-15 signaling prevents normal NK cell development, adding to the T and B cell deficiency caused by the Prkdc^scid mutation ^[6].

The permissiveness of these hosts reflects several complementary features ^[2]:

• Absence of functional NK cells. This removes an important barrier to human cell engraftment.
• Reduced innate rejection inherited from the NOD background. The NOD SIRPα variant binds human CD47, helping deliver an inhibitory signal that reduces macrophage-mediated clearance of human cells ^{[3, 6]}. The NOD background also carries C5 deficiency.
• Profound adaptive immune deficiency. The combined effects of the scid mutation and disrupted Il2rg signaling strongly restrict the development of functional mouse lymphocytes.

Studies of related strains, including NSG, have also demonstrated reduced thymic lymphoma limitations and support for long-term human hematopoietic engraftment. Lifespan and tumor-incidence claims for individual strains should be based on strain-specific data.

NKG mice support transplantation of human tumor cell lines, patient-derived tumor tissues, hematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs), and other selected human cells and tissues. The usable study window depends on the graft, conditioning regimen, disease progression and development of graft-versus-host disease (GvHD) ^[1-2].

Next-generation strains

Newer strains build on severely immunodeficient platforms to support specific human cell lineages or extend experimental applications ^[6]:

• Human cytokine expression: factors such as IL-3, GM-CSF and SCF can improve support for selected hematopoietic lineages, while human IL-15 can support human NK cells.
• Mouse MHC knockout: loss of mouse MHC class I and/or class II can reduce or delay xenogeneic GvHD, particularly in PBMC-humanized models.
• Selected Kit mutations: these can support human HSC engraftment without irradiation conditioning in appropriately engineered strains.

Choosing a Host for Immunotherapy Research: Applications of NKG Mice

The host strain is an important variable in an in vivo immunotherapy study. Residual immunity can restrict human cell engraftment, while host health, tumor burden and GvHD can limit the observation period ^[1]. Because NKG mice lack mature T cells, B cells and functional NK cells, they provide a suitable host platform for the following applications.

CAR-T cell therapy

NKG mice can be engrafted with human tumors and then infused with human CAR-T cells to assess anti-tumor efficacy, CAR-T expansion and persistence. Because infused human T cells can induce xenogeneic GvHD over time, study duration and endpoints should account for this risk ^{[1, 6]}. Their ability to model human cytokine-mediated toxicities and broader immune interactions is limited and depends on the degree of human immune system reconstitution.

These models evaluate CAR-T activity within a defined xenograft setting and do not reproduce every aspect of human immunity or clinical toxicity ^[1].

Patient-derived xenografts (PDX)

NKG mice can host human tumor tissue that engrafts poorly in less immunodeficient strains. PDX models can retain key features of the original tumor, including histology and aspects of tumor heterogeneity, making them useful for drug efficacy studies and translational research ^[8].

Engraftment rates vary by tumor type, sample quality and implantation conditions. Tumor composition can also change during engraftment and passage, so model identity and relevant tumor characteristics should be checked over time ^[8].

Humanized immune system (HIS) models

NKG mice can be engrafted with human cells to generate models carrying components of the human immune system ^{[2, 6]}:

• HSC-humanized models: human CD34⁺ hematopoietic stem and progenitor cells can reconstitute multiple human immune lineages over several months, supporting longer-term studies.
• PBMC-humanized models: human PBMC transplantation produces rapid engraftment dominated by human T cells, supporting shorter-term studies. Xenogeneic GvHD limits the experimental window.

The extent and function of immune reconstitution depend on the donor cells, host strain and experimental protocol. These models do not fully reproduce the human immune system, and additional modifications may be needed to support specific cell populations or immune functions ^{[1, 6]}.

Figure 2. Workflow for the preclinical evaluation of cancer and immunization using a HIS mice platform ^[4].

Long-term and other studies

For studies assessing treatment durability, the experimental window should be established for the specific NKG-based model rather than inferred from the host strain alone.

Depending on the human cells or tissues engrafted and any additional genetic modifications, NKG-based models can support research on hematopoiesis, blood disorders, infectious diseases such as HIV, selected autoimmune mechanisms, vaccine responses and GvHD ^[2]. They may also support selected safety endpoints when the relevant human target and responding cells are present.

Find the Right Immunodeficient Model for Your Study

There is no single best immunodeficient mouse. Start from your research objective:

• Readily engrafting CDX models: BALB/c nude mice are often sufficient for fast-growing, well-characterized cell lines. If take rates are low or tumor growth is inconsistent, moving to NKG mice can improve engraftment and reduce group-to-group variability.
• PDX and hematologic tumors: patient-derived tissue and blood cancers typically need a host lacking T, B and functional NK cells. NKG mice provide this level of immunodeficiency, helping you make the most of limited patient samples.
• CAR-T xenografts: meaningful efficacy data depend on reliable tumor engraftment and sustained human T cell expansion. NKG mice support both, giving a defined window to measure tumor control and CAR-T persistence before xenogeneic GvHD develops.
• Humanized immune system studies: PBMC-humanized NKG mice offer rapid human T cell engraftment for short-term studies. For checkpoint inhibitors, tumor vaccines, ADCC and other studies that need a broader human immune repertoire, huHSC-NKG-ProF mice reconstitute both human lymphoid and myeloid lineages, providing a more complete human immune system for longer-term studies.

Figure 3. The generation of common preclinical murine cancer models ^[9].

Selecting an appropriate immunodeficient mice can improve the suitability of xenograft experiments and help researchers obtain more interpretable preclinical data.

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References

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[2] Chen J, Liao S, Xiao Z, Pan Q, Wang X, Shen K, Wang S, Yang L, Guo F, Liu HF, Pan Q. The development and improvement of immunodeficient mice and humanized immune system mouse models. Front Immunol. 2022 Oct 19;13:1007579. doi: 10.3389/fimmu.2022.1007579. PMID: 36341323; PMCID: PMC9626807.

[3] Lee J, Jung J. Considerations for selecting immunodeficient mouse strains for cancer xenograft models. Lab Anim Res. 2026;42:30. doi: 10.1186/s42826-026-00292-8.

[4] Chiang PC, Lee-Chan H, Lee YL. Establishing human immune system mice: application, opportunity, and challenges. Exp Mol Med. 2026 Jul;58(7):2097-2112. doi: 10.1038/s12276-026-01777-1. Epub 2026 Jul 3. PMID: 42399657; PMCID: PMC13434040.

[5] Szadvari I, Krizanova O, Babula P. Athymic nude mice as an experimental model for cancer treatment. Physiol Res. 2016 Dec 21;65(Suppl 4):S441-S453. doi: 10.33549/physiolres.933526. PMID: 28006926.

[6] Martinov T, McKenna KM, Tan WH, Collins EJ, Kehret AR, Linton JD, Olsen TM, Shobaki N, Rongvaux A. Building the Next Generation of Humanized Hemato-Lymphoid System Mice. Front Immunol. 2021 Feb 22;12:643852. doi: 10.3389/fimmu.2021.643852. PMID: 33692812; PMCID: PMC7938325.

[7] Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL, et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995 Jan 1;154(1):180-91. PMID: 7995938.

[8] Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther. 2023 Apr 12;8(1):160. doi: 10.1038/s41392-023-01419-2. PMID: 37045827; PMCID: PMC10097874.

[9] Bareham B, Georgakopoulos N, Matas-Céspedes A, Curran M, Saeb-Parsy K. Modeling human tumor-immune environments in vivo for the preclinical assessment of immunotherapies. Cancer Immunol Immunother. 2021 Oct;70(10):2737-2750. doi: 10.1007/s00262-021-02897-5. Epub 2021 Apr 8. PMID: 33830275; PMCID: PMC8423639.