BRGS TSLP mouse
Immunodeficient mouse for immunology and oncology research
Model characteristics
Type :
Mutant inbred mouse, Mus musculus, GMO
Use of this strain is restricted to private sector users
Strain name:
C-Rag2tm1Fwa-Il2rgtm1Cgn-SirpαNOD -Tg TSLP
Origin:
Institut Pasteur, France, 2022
Colour and related genotype:
Albino mouse
Breeding:
Cryo, In vitro, In vivo
Description of our model and application areas
The BRGS TSLP mouse model or Balb/c Rag2 γc Sirpα TSLP strain is a severely immunodeficient inbred (Balb/c background) strain model with 2 knock out (KO) genetic mutations and a NOD background gene: the γc KO gene (Interleukin 2 receptor gamma chain, IL2rgTm1), the Rag2 KO gene (recombinase 2 activating gene), and the Sirpα (NOD Background) gene. This model also carries a transgene expressing the molecule: thymic-stromal-cell-derived lymphopoietin.
The Rag2Tm1 mutation, commonly known as Rag2, is a KO mutation in the gene coding for the recombinase 2 enzyme, which plays a key role in the generation of T and B receptors in lymphocytes. This absence blocks the development of T and B lymphocytes and induces an immune deficiency. Mice wich are homozygous for this mutation show a complete absence of T and B lymphocytes in the periphery.
The IL2rgTm1 mutation called γc is a KO mutation of the gene encoding the gamma c chain common to (among others) interleukins (IL-2, IL-4, IL-7, IL-9 and IL-15). This gene is required for the differentiation and function of many haematopoietic cells with a complete impact on the development of Natural Killer (NK) cells.
The combination of these two mutations, em>Rag2Tm1–IL2rgTm1 , induces a severe immunodeficiency with absence of T, B and NK lymphocyte compartments.
The BRGS TSLP mouse model carries the Sirpα gene from the NOD background with a particular polymorphism. Expression of the Sirpα protein (NOD fund alleles) on the surface of bone marrow macrophages allows high-affinity binding to CD47 markers of human haematopoietic cells.
This binding induces a “don’t eat me” signal that blocks murine macrophages and prevents phagocytosis of transplanted human cells.
This is a notable feature of the NOD background (transferred by backross to BRG Balb/c mutants) that gives it an advantage in human transplantation and xenografting in general.
The BRGS TSLP mouse model carries the TSLP transgene, thymic-stromal-cell-derived lymphopoietin, to restore the development of secondary lymphoid nodes absent in the so-called γc KO models (Interleukin 2 receptor gamma chain, IL2rgTm1 ) and whatever the genetic background. This absence of peripheral lymph nodes is related to the absence of lymphoid tissue inducer dependent on γc receptor mediated signals.
The BRGS TSLP mouse model differs from the NXG strains (NOD-Prkdcscid–IL2rgTm1/Rj) by the absence of the Prkdcscid mutation, commonly referred to as “SCID” for Severe Combinated Immunodeficiency. The BRGS T strain is thus more resistant to irradiation, injection of genotoxic products and stress, conferring a more stable and durable use to the xenograft in general, and carry peripheral lymph nodes, allowing an optimization of the xenografts of the human immune system, by increasing the quality, quantity and functionality of the actors of the immunity.
JANVIER LABS has licensed the BRGS TSLP mouse model from the Institut Pasteur.
The animals are bred to maintain both the genetic background and the mutations of interest in their homozygous forms. The BRGS TSLP mouse model is bred in inbred mode and the phenotype is controlled in accordance with the JANVIER LABS GENETIC POLICY®.
Main application and research fields
Phenotypic characterisation
This model has been entirely characterized. The immunological and hematological parameters were characterized by Center of Immunophenomics (Ciphe, Marseille, France).
Flow cytometry analysis, spleen
Representative flow cytometry analysis confirming the absence of positive B cells (CD19), positive T cells (CD4 and CD8) and NK cells (CD335) in the peripheral blood of BRGS TSLP mice.
- Fluorescence intensities (MFI) represent specific expressions of clusters of differentiations.
- Clouds of points are obtained, each point representing a cell.
- We can then determine the negative/single and positive/double positive cells in each populations (defined by « Cluster of Differentiation ») , fixing or not the two antibodies carrying the fluorochromes.
Phenotypical / Physiological observations
The BRGS TSLP mouse model are viable, fertile, of normal size, and show no obvious physical or behavioral abnormalities.
The BRGS TSLP mouse model levels were elevated in the serum of adult BRGS TSLP mice expressing K14 promoter-driven mouse TSLP compared with those in BRGS TSLP mice. Whereas gut NK cell and ILC (Innate Lymphoid Cells) subsets were severely depleted in Il2rg−/− BRGS TSLP mice compared with numbers in Rag2−/− mice, BRGS TSLP mice showed improved ILC development with no effect on NK cells, suggesting that TSLP complements IL-7 signaling pathways in vivo. Previous studies showed that TSLP overexpression can restore Lymphoid Tissue inducer (LTi) cell function in Il2rg−/− hosts.
This finding have been confirmed in BRGS TSLP mice, in which Lymph Node (LN) anlagen robustly developed throughout the body.
The few LN anlagens in BRGS TSLP mice were smaller than those in BRGS TSLP mice and visible only through dye staining.
In contrast, the defective Peyer’s patches (PP) development secondary to Il2rg knockout was not rescued by TSLP overexpression.
BRGS TSLP mice are deficient in mature lymphocytes, and serum immunoglobulinsis not detectable. These mice are resistant to the development of lymphomas even after treatment with sublethal radiation. These mutant mice have been shown to readily support the transplantation of human CD34+ hematopoietic stem cells and represent a superior long-lived model suitable for studies using xenotransplantation strategies.
Origin / Creation
The BRGS TSLP model was generated at the Institut Pasteur.
The TSLP transgen expression is under the K14 control promoter, and previously created on the C57BL/6 genetic background.
TSLP transgenic mice were extensively back-crossed (> 10 generations) to the Balb/c Rag2−/−-Il2rg−/−-Rag2 γc Sirpα strain (BRGS) to create TSLP-transgenic BRSG (BRGST) hosts.
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