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Strain Name:

B6.Cg-Tg(Cd4-TGFBR2)16Flv/J

Stock Number:

005551

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Genes & Alleles   Cd4;   TGFBR2;   Tg(Cd4-TGFBR2)16Flv;

Product Information

Strain Details

Type JAX® GEMM® Strain - Congenic
Additional information on JAX® GEMM® Strains.
Type JAX® GEMM® Strain - Mutant Strain
Type JAX® GEMM® Strain - Transgenic
Mating SystemInbred x Hemizygote         (Female x Male)
Specieslaboratory mouse
Donating Investigator Richard Flavell,   Yale University School of Medicine
GenerationN15+6 (08-JAN-08)

Strain Description
These transgenic mice express a dominant-negative form of the human transforming growth factor, beta receptor II (dnTGFBRII) under the direction of the mouse CD4 antigen promoter. Transgene expression is detected by RT-PCR analysis of thymus tissue, and is at a level sufficient to block TGF-beta signaling specifically in CD4+ and CD8+ T cells. At 3 to 4 months of age transgenic mice begin to display wasting and diarrhea. Histological examination reveals inflammatory bowel disease (IBD) and inflammatory infiltration of the large intestine, lungs, and liver. Less severe infiltration is observed in the stomach, duodenum, pancreas and kidney. The Donating Investigator indicates that the severity of and organs affected by the IBD is influenced by strain background. Western blot analysis detects circulating autoreactive antibodies. IgG immune deposits form in kidney glomeruli. There is a 3-fold increase in total cell numbers in peripheral lymphoid organs. T cells spontaneously differentiate into Th1 or Th2 cytokine secreting cells. Transgenic mice do not develop tumors when challenged with some TGF-beta producing tumor cells. Mice hemizygous for the transgenic insert are viable and fertile. Hemizygous female mice do not support pregnancies well. This mutant mouse strain may be useful in studies of autoimmune disease, anti-tumor immune response, and inflammatory bowel disease.

Strain Development
A transgenic construct containing sequence between nucleotides -7 and +573 of the human transforming growth factor, beta receptor II (70/80kDa) gene under the direction of the mouse CD4 antigen promoter was microinjected into B6C3HF1 fertilized oocytes. The resulting founder animals were backcrossed to B10.BR mice for 3 gernations, then backcrossed to C57BL/6 mice for 15 generations.

Related Disease (OMIM) Terms

Inflammatory Bowel Disease 11; IBD11
Mammalian Phenotype Terms assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Tg(Cd4-TGFBR2)16Flv/?

        involves: C3H * C57BL/6 * C57BL/10 * C57BR/cd
  • growth/size phenotype
  • cachexia (MGI Ref ID J:97554)
    • starting about 3 to 4 months of age, mice begin wasting due to an autoimmune disease
  • immune system phenotype
  • abnormal T cell activation (MGI Ref ID J:97554)
    • all CD8 T cells and most CD4 T cells are in an activated, effector state with CD8 T cells producing IFN-gamma and CD4 T cells producing Th1 and/or Th2 cytokines
    • abnormal T cell proliferation (MGI Ref ID J:97554)
      • in vitro stimulated CD4- and CD8- T cells are refractory to the inhibitory effects of TGF-beta1 and TGF-beta3 on T cell proliferation
      • there is only a slight inhibition of proliferation on activated T cells by TGF-beta2
  • abnormal thymic involution (MGI Ref ID J:97554)
    • thymuses of 5 month old mice are completely involuted with only thymic lymph nodes detectable in the area where the thymus in normally present
  • decreased B cell number (MGI Ref ID J:97554)
    • there is a decrease in the percentage of B cells found in the spleen though due to the increase in spleen cellularity the total number of B cells is normal
  • increased anti-nuclear antigen antibody level (MGI Ref ID J:97554)
    • auto-antibodies to nuclear proteins are detected in the sera of mice with specificity of these antibodies differing between individual mice
  • increased immunoglobulin level (MGI Ref ID J:97554)
    • increased IgA level (MGI Ref ID J:97554)
      • sera levels of IgA are 16 fold higher in 5-6 month old mice than in age matched wild-type mice
    • increased IgG1 level (MGI Ref ID J:97554)
      • sera levels of IgG1 are 8 fold higher in 5-6 month old mice than in age matched wild-type mice
    • increased IgG2a level (MGI Ref ID J:97554)
      • sera levels of IgG2a are 4 fold higher in 5-6 month old mice than in age matched wild-type mice
  • increased inflammatory response (MGI Ref ID J:97554)
    • colitis (MGI Ref ID J:97554)
      • pronounced inflammation in the gut is evident in 5 month old mice with dense infiltrates of lymphocytes, macrophages and plasma cells occurring in the lamina propia and mucosal epithelia
      • the inflammation also causes distortion of the crypt architecture, crypt abscesses and compensatory epithelial hyperplasia
      • mild inflammation is also evident in the stomach and duodenum
    • glomerulonephritis (MGI Ref ID J:97554)
      • IgG deposits are found in the kidney glomeruli of 5 month old mice
      • mild infiltration of inflammatory cells is also observed
    • liver inflammation (MGI Ref ID J:97554)
      • there are clusters of macrophages and lymphocytes located in the parenchyma and adjacent to blood vessels in the liver of 5 month old mice
    • lung inflammation (MGI Ref ID J:97554)
      • lungs of 5 month old mice have focal perivascular and intraalveolar infiltration of lymphocytes and macrophages
    • pancreas inflammation (MGI Ref ID J:97554)
      • mild inflammation is evident in the pancreas of 5 month old mice
  • increased memory T cell number (MGI Ref ID J:97554)
    • 90% of the T cells found in the spleen of 5 month old mice are CD62Llow CD44high indicating an activated/memory phenotype
    • increases in memory T cell numbers are found as early as 4 weeks of age
  • lymph node hyperplasia (MGI Ref ID J:97554)
    • there is a 3-fold increase in the number of cells found in the lymph nodes
  • spleen hyperplasia (MGI Ref ID J:97554)
    • total cell number in the spleen is increased by about 60%
  • digestive/alimentary phenotype
  • colitis (MGI Ref ID J:97554)
    • pronounced inflammation in the gut is evident in 5 month old mice with dense infiltrates of lymphocytes, macrophages and plasma cells occurring in the lamina propia and mucosal epithelia
    • the inflammation also causes distortion of the crypt architecture, crypt abscesses and compensatory epithelial hyperplasia
    • mild inflammation is also evident in the stomach and duodenum
  • diarrhea (MGI Ref ID J:97554)
    • mice start developing diarrhea at about 3 to 4 months of age
  • pancreas inflammation (MGI Ref ID J:97554)
    • mild inflammation is evident in the pancreas of 5 month old mice
  • endocrine/exocrine gland phenotype
  • pancreas inflammation (MGI Ref ID J:97554)
    • mild inflammation is evident in the pancreas of 5 month old mice
  • hematopoietic system phenotype
  • abnormal T cell activation (MGI Ref ID J:97554)
    • all CD8 T cells and most CD4 T cells are in an activated, effector state with CD8 T cells producing IFN-gamma and CD4 T cells producing Th1 and/or Th2 cytokines
    • abnormal T cell proliferation (MGI Ref ID J:97554)
      • in vitro stimulated CD4- and CD8- T cells are refractory to the inhibitory effects of TGF-beta1 and TGF-beta3 on T cell proliferation
      • there is only a slight inhibition of proliferation on activated T cells by TGF-beta2
  • abnormal thymic involution (MGI Ref ID J:97554)
    • thymuses of 5 month old mice are completely involuted with only thymic lymph nodes detectable in the area where the thymus in normally present
  • decreased B cell number (MGI Ref ID J:97554)
    • there is a decrease in the percentage of B cells found in the spleen though due to the increase in spleen cellularity the total number of B cells is normal
  • increased memory T cell number (MGI Ref ID J:97554)
    • 90% of the T cells found in the spleen of 5 month old mice are CD62Llow CD44high indicating an activated/memory phenotype
    • increases in memory T cell numbers are found as early as 4 weeks of age
  • spleen hyperplasia (MGI Ref ID J:97554)
    • total cell number in the spleen is increased by about 60%
  • liver/biliary system phenotype
  • liver inflammation (MGI Ref ID J:97554)
    • there are clusters of macrophages and lymphocytes located in the parenchyma and adjacent to blood vessels in the liver of 5 month old mice
  • renal/urinary system phenotype
  • glomerulonephritis (MGI Ref ID J:97554)
    • IgG deposits are found in the kidney glomeruli of 5 month old mice
    • mild infiltration of inflammatory cells is also observed
  • respiratory system phenotype
  • lung inflammation (MGI Ref ID J:97554)
    • lungs of 5 month old mice have focal perivascular and intraalveolar infiltration of lymphocytes and macrophages

Tg(Cd4-TGFBR2)16Flv/?

        involves: C3H * C57BL/6
  • digestive/alimentary phenotype
  • colitis (MGI Ref ID J:134156)
    • colitis is observed in mice 3-4 months of age with ulcerations found near the iliel-cecal junction, the ascending-to-descending colon transition and the anal-rectal junction
  • immune system phenotype
  • abnormal CD8-positive, alpha-beta regulatory T cell morphology (MGI Ref ID J:134473)
    • CD8 T cells fail to express FoxP3 when cultured under conditions that normally generate regulatory CD8 T cells (high costimulation and TGF-beta signaling)
  • abnormal T cell proliferation (MGI Ref ID J:134473)
    • TGF-beta is unable to increase proliferation of in vitro activated CD8 T cells
  • colitis (MGI Ref ID J:134156)
    • colitis is observed in mice 3-4 months of age with ulcerations found near the iliel-cecal junction, the ascending-to-descending colon transition and the anal-rectal junction
  • increased interferon-gamma secretion (MGI Ref ID J:134156)
    • there is an increase in the percentage of CD8 T cells producing IFN-gamma compared to wild-type mice there is an increase in the percentage of CD8 T cells producing IFN-gamma compared to wild-type mice
  • increased tumor necrosis factor secretion (MGI Ref ID J:134156)
    • 32.6% of T cells produce TNF compared to 23.8% of wild-type mice
  • hematopoietic system phenotype
  • abnormal CD8-positive, alpha-beta regulatory T cell morphology (MGI Ref ID J:134473)
    • CD8 T cells fail to express FoxP3 when cultured under conditions that normally generate regulatory CD8 T cells (high costimulation and TGF-beta signaling)
  • abnormal T cell proliferation (MGI Ref ID J:134473)
    • TGF-beta is unable to increase proliferation of in vitro activated CD8 T cells

Gene & Allele Details

Allele Symbol Tg(Cd4-TGFBR2)16Flv
Allele Name transgene insertion 16, Richard A Flavell
Common Name(s) CD4-dnTGFBRII; CD4dn-TGF-RII; CD4dnTGFbetaRII; dnTGF-betaRII; dnTGFbetaRII; dnTbetaRII;
Mutation Made By Elizabeth Eynon,   HHMI/ Yale University
Strain of OriginC57BL/6 x C3H
Expressed Gene TGFBR2, transforming growth factor, beta receptor II (70/80kDa), human
Promoter Cd4, CD4 antigen, rat
Molecular Note This transgene contains the mouse CD4 antigen promoter, sequence encoding the extracellular and transmembrane regions, nucleotides -7 and +573, of the human transforming growth factor, beta receptor II (70/80kDa) and a polyadenlylation signal. Transgene expression is detected by RT-PCR analysis of thymus tissue, and is at a level sufficient to block TGF-beta signaling specifically in T cells. [MGI Ref ID J:97554]

Control Information

  Control
   Noncarrier
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Genotyping Protocols

Tg(Cd4-TGFBR2)16Flv

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, these mice are bred as hemizygotes. The Donating Investigator recommends either using only male mice for breeding or fostering pups as hemizygous female mice do not support pregnancies well. These transgenic mice have a reduced lifespan due to autoimmune disease. The Donating Investigator recommends prophylactic antibiotic treatment (for example, Sulfatrim).
Diet Information LabDiet® 5K52/5K67

Related Strains

Strains carrying other alleles of Cd4
004687   C.Cg-Tg(SKP2)4Paga/J
005334   NOD/ShiLt-Tg(Cd4-EGFP)1Lt/J
View Strains carrying other alleles of Cd4     (2 strains)

Additional Web Information

Congenic Nomenclature

Animal Health Reports

Room Number           AX11

Research Applications

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

Cancer Research
Tumor Resistance

Immunology and Inflammation Research
Inflammation (Inflammatory bowel disease)

References

Selected Reference(s)

Gorelik L; Flavell RA. 2000. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171-81. [PubMed: 10714683]  [MGI Ref ID J:97554]

Additional References

Price and Supply Information

Strain Name: B6.Cg-Tg(Cd4-TGFBR2)16Flv/J
Stock Number: 005551

Price Details

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Supply Details

Standard SupplyRepository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.
Supply Notes Usually shipped between four and eight weeks of age.
This strain is included in the Induced Mutant Resource Colony collection.
LicensingSee General Terms and Conditions below for Licensing and Use Restrictions  
Control InformationView Control Information in Strain Details.

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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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