Overview

Also Known As: Foxp3^DTR

Foxp3^DTR mutant mice express knocked-in human diphtheria toxin receptor and EGFP genes from the Foxp3 locus--without disrupting expression of the endogenous Foxp3 gene. These mice may be useful for regulatory T cell visualizing and ablation.

Donating Investigator

Alexander Rudensky, Memorial Sloan Kettering Cancer Center

Genetic overview

Genetic Background	Generation
	N8+pN2F1 (2019-03-01 00:00:00)

Foxp3^{tm3(DTR/GFP)Ayr}

Allele Type	Gene Symbol	Gene Name
Targeted (Reporter, Inserted expressed sequence)	Foxp3	forkhead box P3

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Research Applications

Research Tools
Immunology, Inflammation and Autoimmunity Research

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Base Price

Starting at:

$0.00 Domestic price for male 4-week

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Details

Detailed Description

Foxp3^DTR mutant mice contain an internal ribosome entry site (IRES), a human diphtheria toxin receptor (DTR), and an enhanced green fluorescent protein (EGFP) downstream of the internal stop codon of the forkhead box P3 (Foxp3) gene. FOXP3 is a transcription factor required for the development and function of regulatory T (T _reg) cells, which are required for suppression of self-reactive T cells and prevention of some autoimmune diseases. In these mice, DTR-EGFP expression is evident in FOXP3⁺ T_reg cells. Diphtheria toxin (DT) administration results in ablation of T_reg cells in thymus, lymph nodes, and spleen 2 days after injection, with cell numbers rebounding 10-15 days post-injection. Neonates injected with DT daily all die from lymphoproliferative disease, indicated by failure to thrive, lack of mobility, ventral skin lesions, hunched posture, and conjunctivitis, within 27 days of birth. With the same DT treatment, adults exhibit a more rapid development of autoimmune disease and die within 3 weeks. These mice show an increase in CD4⁺ T cell activation, as well as an increase in the number of B cells, macrophages, granulocytes, natural killer, and dendritic cells in the spleen and lymph nodes. Homozygous females and hemizygous males are viable, fertile, and normal in size. These mice may be useful for visualizing and specifically eliminating regulatory T cells, and for studying autoimmunity and immune dysfunction.

Development

The Foxp3^DTR targeting vector was designed with an internal ribosome entry site (IRES), a human diphtheria toxin receptor (DTR), and an enhanced green fluorescent protein (EGFP), followed by a frt-flanked neomycin (neo) resistance cassette inserted downstream of the internal stop codon of the X-linked forkhead box P3 (Foxp3) gene. This construct was injected into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The donating investigator reported that the resulting mice were backcrossed to C57BL/6NTac mice for at least 8 generations (see SNP note below). Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generation.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a C57BL/6 genetic background.

Expression Data

Expressed Gene	DTR/EGFP, Simian Diphtheria Toxin Receptor; Enhanced Green Fluorescent Protein,
Site of Expression	DTR-EGFP expression is evident in regulatory T cells.

Control Suggestions

Approximate Controls

005304 C57BL/6NJ

Additional Information

Considerations for Choosing Controls

Selected References

Kim JM; Rasmussen JP; Rudensky AY. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191-7PubMed: 17136045 MGI: J:117743

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Genetics

Foxp3^{tm3(DTR/GFP)Ayr}

Allele Symbol: Foxp3^{tm3(DTR/GFP)Ayr}

Allele Name	targeted mutation 3, Alexander Y Rudensky
Allele Type	Targeted (Reporter, Inserted expressed sequence)
Allele Synonym(s)	targeted mutation 3, Alexander Y Rudensky; Foxp3^{tm3(DTR/GFP)Ayr}
Gene Symbol and Name	Foxp3, forkhead box P3
Gene Synonym(s)	AIID; sf; DIETER; IPEX; PIDX; scurfin; XPID; JM2; scurfy; RGD1562112
Expressed Gene	DTR/EGFP, Simian Diphtheria Toxin Receptor; Enhanced Green Fluorescent Protein,
Site of Expression	DTR-EGFP expression is evident in regulatory T cells.
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	X
Molecular Note	A targeting vector was designed to insert an IRES-DTR-GFP with a floxed neo downstream of exon 11.
Mutations Made By	Alexander Rudensky, Memorial Sloan Kettering Cancer Center

Disease/Phenotype

Disease Terms

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Research Tools
- Genetics Research
  - Tissue/Cell Markers
- Fluorescent Proteins
Immunology, Inflammation and Autoimmunity Research
- Lymphoid Tissue Defects
- Autoimmunity
- Immunodeficiency
- Inflammation

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Foxp3^{tm3(DTR/GFP)Ayr}/Foxp3^{tm3(DTR/GFP)Ayr}
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

bradykinesia
- moribund newborns and adults treated with DT display lack of mobility

immune system phenotype

abnormal CD4-positive, alpha-beta T cell physiology
- Foxp3-null CD4+ T cells from DT-treated female mutants have higher T cell activation marker levels than cells from treated controls, as well as proliferation markers

abnormal dendritic cell physiology
- in mutants after T_reg ablation

conjunctivitis
- newborns treated with DT 12 hours after birth exhibit conjunctivitis; adults treated with DT show severe conjunctivitis

decreased T cell number
- after injection
- injection of 50 ug/kg DT at 0 and 24 hours almost completely eliminates all regulatory T cells (T_reg) in 2 days
- thymic T cells rebound to 47% of pre-treatment numbers after 4 days and recovers fully by 10 days; peripheral (lymph nodes and spleen) (T_reg) numbers recover to 8 and 6% by 2 days and fully recover to pre-treatment levels between 10 and 15 days after injection

dermatitis
- massive lymphocytic and mononuclear infiltrates in epidermis seen at 3 weeks with DT treatment

enlarged spleen
- also seen in 3-month old adult mutants treated with DT
- observed in 3-week old mutants treated daily with DT

increased dendritic cell number
- numbers are elevated after T_reg ablation

increased susceptibility to autoimmune disorder
- female mutants treated with DT rapidly develop terminal autoimmune disease resulting from (T_reg) elimination; adult mice develop disease more rapidly than newborn mutants

liver inflammation
- massive lymphocytic and mononuclear infiltrates in liver sinusoids seen at 3 weeks with DT treatment

lung inflammation
- massive lymphocytic and mononuclear infiltrates in lung interstitium seen at 3 weeks with DT treatment

lymph node inflammation
- also seen in 3-month old adult mutants treated with DT
- observed in 3-week old mutants treated daily with DT compared to untreated mutant littermates

growth/size/body region phenotype

cachexia
- occurs in newborn and adult mutants upon DT treatment

weight loss
- observed in newborn and adult mutants treated with DT

integument phenotype

dermatitis
- massive lymphocytic and mononuclear infiltrates in epidermis seen at 3 weeks with DT treatment

liver/biliary system phenotype

liver inflammation
- massive lymphocytic and mononuclear infiltrates in liver sinusoids seen at 3 weeks with DT treatment

mortality/aging

increased sensitivity to induced morbidity/mortality
- adult female mutants treated with DT become moribund beginning at 10 days post-injection and all are dead after 3 weeks of treatment (regulatory T cell ablation)
- remaining treated female mutants at weaning are moribund within 27 days of age
- with injection of diptheria toxin (DT) in newborns at 12 hours after birth and then every other day thereafter, 40% of mutants become moribund by 24 days

respiratory system phenotype

lung inflammation
- massive lymphocytic and mononuclear infiltrates in lung interstitium seen at 3 weeks with DT treatment

vision/eye phenotype

conjunctivitis
- newborns treated with DT 12 hours after birth exhibit conjunctivitis; adults treated with DT show severe conjunctivitis

hematopoietic system phenotype

abnormal CD4-positive, alpha-beta T cell physiology
- Foxp3-null CD4+ T cells from DT-treated female mutants have higher T cell activation marker levels than cells from treated controls, as well as proliferation markers

decreased T cell number
- after injection
- injection of 50 ug/kg DT at 0 and 24 hours almost completely eliminates all regulatory T cells (T_reg) in 2 days
- thymic T cells rebound to 47% of pre-treatment numbers after 4 days and recovers fully by 10 days; peripheral (lymph nodes and spleen) (T_reg) numbers recover to 8 and 6% by 2 days and fully recover to pre-treatment levels between 10 and 15 days after injection

enlarged spleen
- also seen in 3-month old adult mutants treated with DT
- observed in 3-week old mutants treated daily with DT

increased dendritic cell number
- numbers are elevated after T_reg ablation

References

Kim JM; Rasmussen JP; Rudensky AY. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8(2):191-7PubMed: 17136045 MGI: J:117743

Additional References

Harrison OJ; Linehan JL; Shih HY; Bouladoux N; Han SJ; Smelkinson M; Sen SK; Byrd AL; Enamorado M; Yao C; Tamoutounour S; Van Laethem F; Hurabielle C; Collins N; Paun A; Salcedo R; O'Shea JJ; Belkaid Y. 2019. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363(6422)PubMed: 30523076 MGI: J:271547

Additional - Foxp3^{tm3(DTR/GFP)Ayr} related

Technical Support

Contact Technical Support

Genotyping Protocols
- SEPARATED MELT: Foxp3^tm3Ayr alternate2
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

This mutant allele is located on the X chromosome. When maintaining a live colony, homozygous females may be bred with hemizygous males.
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Hemizygote
Citation
When using the Foxp3^DTR mouse strain in a publication, please cite the originating article(s) and include JAX stock #016958 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX18 (Maximum)

Pricing & Availability

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Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Not-For-Profit & Academic Pricing

Service	Genotype	Price
	X linked - Heterozygous females and wildtype males for Foxp3<tm3Ayr>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Also Known As: Foxp3DTR

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Foxp3tm3(DTR/GFP)Ayr

Allele Symbol: Foxp3tm3(DTR/GFP)Ayr

Disease Terms

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Foxp3tm3(DTR/GFP)Ayr/Foxp3tm3(DTR/GFP)Ayrinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

immune system phenotype

growth/size/body region phenotype

integument phenotype

liver/biliary system phenotype

mortality/aging

respiratory system phenotype

vision/eye phenotype

hematopoietic system phenotype

References

Additional References

Additional - Foxp3tm3(DTR/GFP)Ayr related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Not-For-Profit & Academic Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As: Foxp3^DTR

Foxp3^{tm3(DTR/GFP)Ayr}

Allele Symbol: Foxp3^{tm3(DTR/GFP)Ayr}

Genotype: Foxp3^{tm3(DTR/GFP)Ayr}/Foxp3^{tm3(DTR/GFP)Ayr}
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Additional - Foxp3^{tm3(DTR/GFP)Ayr} related