Description

Strain Information

Type Coisogenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Hemizygote         (Female x Male) Species laboratory mouse Generation ?+N1+F2N2 (03-DEC-07)   Donating Investigator Michael Caligiuri,   The Ohio State University

Description
Mice hemizygous for this transgene are viable and fertile. The transgene was designed to optimize the overexpression of secreted, mature interleukin-15. Transgenic IL-15 expression has a similar tissue distribution as the endogenous gene, but at a significantly higher level. IL-15 protein is detectable in the serum from most mutant, but not from wildtype, mice. Mutant mice develop a progressive alopecia by as early as 5-6 weeks of age, with skin lesions appearing over time. While all transgenic mice exhibit early polyclonal/benign expansion of natural killer and memory CD8⁺ T lymphocytes (T/NK), two distinct phenotypes emerge over time: approximately 70% of the transgenic mice will exhibit polyclonal T/NK progression in multiple tissues, while the remaining 30% are characterized by T/NK clonal expansion in multiple tissues and acute lymphoblastic leukemia (T/NK ALL). Both T/NK phenotypes are fatal within the first year of life. Mice harboring this transgene may be useful in studies related to leukemia, lymphocyte homeostasis, alopecia, and graft-versus-host disease, or as a "pre-leukemia" model to elucidate the role of pro-inflammatory cytokine expression/chronic inflammation in transformation and malignancy.

Development
A mouse interleukin-15 cDNA sequence encoding the mature endogenous protein (nucleotides 610-951) was modified with a C-terminal FLAG epitope. This sequence was then fused immediately downstream of (and in-frame with) the mouse interleukin-2 signal peptide coding sequence. Next, the 3' portion of the human growth hormone (hGH) was spliced downstream and out of frame to maximize transgenic expression in vivo. This entire construct was placed under the control of the mouse MHC class 1 D^d promoter. The resulting 5.2 kb construct was injected into the pronucleus of FVB/N embryos. Embryos were transferred into the oviducts of pseudopregnant ICR foster mothers. Transgenic offspring were bred together for an unknown number of generations before arrival at The Jackson Laboratory.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of H2-D

006611	NOD.129P2(B6)-B2mtm1Unc Tg(HLA-A/H2-D/B2M)1Dvs/DvsJ
006605	NOD.Cg-Prkdcscid Emv30b Tg(HLA-A/H2-D/B2M)1Dvs/DvsJ
006604	NOD/ShiLtDvs-Tg(HLA-A/H2-D/B2M)1Dvs/J

View Strains carrying other alleles of H2-D     (3 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Tg(H2-D-Il15)3304Clgr/?

        FVB/N-Tg(H2-D-Il15)3304Clgr

• life span-post-weaning/aging
• premature death (MGI Ref ID J:67478)
  • between 12 and 30 weeks of age, 70% of transgenic mice exhibit signs of illness - decreased activity, weight loss and breathing difficulty - and within a week become acutely moribund and die or must be euthanized
• immune system phenotype
• abnormal T cell morphology (MGI Ref ID J:67478)
  • the early, benign expansion of CD8⁺CD44^hiLy6c⁺ T cells observed in all transgenic mice is of polyclonal origin
  • whereas absolute numbers of peripheral CD4⁺ T cells are comparable in 6 week old transgenic and control littermates, the number of CD8⁺ T cells is 10-fold greater in transgenic than in control mice
  • flow cytometric analysis of lymphocytes from 22 affected (moribund) mice revealed the expanded population consistently bears the (somewhat heterogeneous) marker signature: CD3⁺TCR-beta⁺CD2⁺CD5⁺CD44⁺CD8^+/-DX5^mixed, although DX5⁺CD3^- NK cells remain elevated
• abnormal T cell subpopulation ratio (MGI Ref ID J:67478)
  • because of the expansion of the CD8⁺ T cell compartment, the ratio of CD4⁺ to CD8⁺ T cells is dramatically skewed toward the CD8⁺ population in transgenic mice (0.59 +/- 0.04 versus 3.26 +/- 0.1 in controls)
• increased memory T cell number (MGI Ref ID J:67478)
  • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44^hi CD62L^loCD69^-Ly6c^hi
• abnormal lymphocyte physiology (MGI Ref ID J:67478)
  • transgenic mice that do not exhibit late clonal lymphocyte expansion nonetheless develop multiorgan lymphocytic infiltration
  • mice with highly elevated lymphocyte counts have lymphocyte infiltration of the peritoneum and intraabdominal organs
• abnormal spleen cellularity (MGI Ref ID J:67478)
  • large numbers of both CD3⁺ T lymphocytes and NK cells invade the spleens of ill mice
• dermatitis (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts exhibit skin inflammation characterized by heavy infiltration of the skin, primarily the dermis, by CD3⁺ lymphocytes and by mast cell infiltration
• enlarged lymph nodes (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts have lymphadenopathy with disruption of the normal nodal architecture
• enlarged spleen (MGI Ref ID J:67478)
  • moribund mice have massive splenomegaly
• increased lymphocyte cell number (MGI Ref ID J:67478)
  • by 6 weeks of age, all transgenic mice exhibit peripheral blood lymphocytosis, with lymphocyte counts averaging 31, 694 +/- 3, 267 /ul of blood versus 7, 983 +/- 503/ ul of control blood
  • between 12 and 30 weeks of age, 70% of transgenic mice demonstrate progression of earlier lymphocytosis, with lymphocyte counts averaging 186,000 +/- 32,433/ul (range 46,000 - 606,000/ul) of blood
  • peripheral blood smears from ill mice contain large numbers of lymphocytes, some with blast-like features and prominent nucleoli
• increased NK cell number (MGI Ref ID J:67478)
  • early lymphocytosis in transgenic mice is due to expansion primarily of functional - in terms of target cell lysis and induced interferon gamma secretion - DX5⁺CD3^-Ly49⁺ natural killer (NK) cells
• increased memory T cell number (MGI Ref ID J:67478)
  • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44^hi CD62L^loCD69^-Ly6c^hi
• increased spleen white pulp amount (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts have expansion of the splenic white pulp
• hematopoietic system phenotype
• abnormal T cell morphology (MGI Ref ID J:67478)
  • the early, benign expansion of CD8⁺CD44^hiLy6c⁺ T cells observed in all transgenic mice is of polyclonal origin
  • whereas absolute numbers of peripheral CD4⁺ T cells are comparable in 6 week old transgenic and control littermates, the number of CD8⁺ T cells is 10-fold greater in transgenic than in control mice
  • flow cytometric analysis of lymphocytes from 22 affected (moribund) mice revealed the expanded population consistently bears the (somewhat heterogeneous) marker signature: CD3⁺TCR-beta⁺CD2⁺CD5⁺CD44⁺CD8^+/-DX5^mixed, although DX5⁺CD3^- NK cells remain elevated
• abnormal T cell subpopulation ratio (MGI Ref ID J:67478)
  • because of the expansion of the CD8⁺ T cell compartment, the ratio of CD4⁺ to CD8⁺ T cells is dramatically skewed toward the CD8⁺ population in transgenic mice (0.59 +/- 0.04 versus 3.26 +/- 0.1 in controls)
• increased memory T cell number (MGI Ref ID J:67478)
  • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44^hi CD62L^loCD69^-Ly6c^hi
• abnormal spleen cellularity (MGI Ref ID J:67478)
  • large numbers of both CD3⁺ T lymphocytes and NK cells invade the spleens of ill mice
• enlarged spleen (MGI Ref ID J:67478)
  • moribund mice have massive splenomegaly
• increased bone marrow cell number (MGI Ref ID J:67478)
  • large numbers of both CD3⁺ T lymphocytes and NK cells invade the bone marrow of ill mice
• increased lymphocyte cell number (MGI Ref ID J:67478)
  • by 6 weeks of age, all transgenic mice exhibit peripheral blood lymphocytosis, with lymphocyte counts averaging 31, 694 +/- 3, 267 /ul of blood versus 7, 983 +/- 503/ ul of control blood
  • between 12 and 30 weeks of age, 70% of transgenic mice demonstrate progression of earlier lymphocytosis, with lymphocyte counts averaging 186,000 +/- 32,433/ul (range 46,000 - 606,000/ul) of blood
  • peripheral blood smears from ill mice contain large numbers of lymphocytes, some with blast-like features and prominent nucleoli
• increased NK cell number (MGI Ref ID J:67478)
  • early lymphocytosis in transgenic mice is due to expansion primarily of functional - in terms of target cell lysis and induced interferon gamma secretion - DX5⁺CD3^-Ly49⁺ natural killer (NK) cells
• increased memory T cell number (MGI Ref ID J:67478)
  • early lymphocytosis of transgenic mice is characterized by a secondary expanded subpopulation bearing the marker signature of memory T cells: CD44^hi CD62L^loCD69^-Ly6c^hi
• increased spleen white pulp amount (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts have expansion of the splenic white pulp
• tumorigenesis
• leukemia (MGI Ref ID J:67478)
  • molecular analysis of Tcrb gene rearrangements defined the late expanded lymphocyte populations of 48% (9/19) of ill transgenic mice as clonal, indicative of T-cell leukemia
  • flow cytometric analysis of lymphocytes from 2 affected (moribund) mice revealed an expanded population of CD3^-TCR-beta^-CD8^-CD4^-DX5⁺ cells proposed to represent NK cell leukemias
  • ~30% of transgenic mice develop clonal expansion of NK/T lymphocytes in multiple tissues that progresses to acute lymphoblastic leukemia (NK/T ALL)
• liver/biliary system phenotype
• abnormal liver morphology (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts have liver involvement characterized by perivascular and sinusoidal lymphocyte infiltration
• enlarged liver (MGI Ref ID J:67478)
  • moribund mice have massive hepatomegaly
• respiratory system phenotype
• abnormal lung morphology (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts have lung involvement ranging from heavy but confined infiltration around blood vessels to generalized infiltration involving the alveolar walls
• skin/coat/nails phenotype
• alopecia (MGI Ref ID J:67478)
  • all mice with this transgene develop progressive alopecia beginning at 4-6 weeks of age, affecting initially the head and forelimbs and eventually 50-90% of the skin surface
• dermatitis (MGI Ref ID J:67478)
  • mice with highly elevated lymphocyte counts exhibit skin inflammation characterized by heavy infiltration of the skin, primarily the dermis, by CD3⁺ lymphocytes and by mast cell infiltration
• epidermal hyperplasia (MGI Ref ID J:67478)
• hair follicle degeneration (MGI Ref ID J:67478)
• hyperkeratosis (MGI Ref ID J:67478)
• spontaneous skin ulceration (MGI Ref ID J:67478)

View Research Applications

Research Applications

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

Cancer Research
Genes Regulating Growth and Proliferation
Growth Factors/Receptors/Cytokines
Increased Tumor Incidence (Leukemia)

Cardiovascular Research
Vascular Defects (defective leukocyte function)

Dermatology Research
Skin and Hair Texture Defects

Immunology and Inflammation Research
Growth Factors/Receptors/Cytokines
Immunodeficiency (NK Cell and Cd8 T Cell defects)

Internal/Organ Research
Lymphoid Tissue Defects

Research Tools
Cancer Research (Leukemia)
Cancer Research (xenograft/transplant host)
Dermatology Research
Immunology and Inflammation Research (T cell deficiency) (xenograft/transplant host)
Toxicology Research (xenograft/transplant host)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(H2-D-Il15)3304Clgr
Allele Name		transgene insertion 3304, Michael A Caligiuri
Allele Type		Transgenic (random, expressed)
Common Name(s)		IL-15tg; IL15tg; Il15-Tg;
Mutation Made By		Michael Caligiuri,   The Ohio State University
Strain of Origin		FVB/N
Expressed Gene		Il15, interleukin 15, mouse, laboratory
Promoter		H2-D, histocompatibility 2, D region, mouse, laboratory
General Note		Posttranscriptional checkpoints that maintain low endogenous wild-type IL15 intra- and extracellular protein levels - a series of 5' AUGs, the poorly translated and secreted IL15 signal peptide sequence and a C-terminal retention signal - have been eliminated from the transgene and replaced with sequences that maximize IL15 expression. (J:67478) Although three transgenic lines were created in the FVB/N background, the phenotype is reported only for line 3304; the others are 3284 and 3285. It is stated that the phenotypes of all three are similar, but differ in severity depending on the level of transgene mRNA expression. (J:67478)
Molecular Note		The coding region of the transgene comprises a cDNA encoding the mature mouse IL15 protein (nt 610-951) joined to the signal peptide-encoding sequence of the mouse IL2 gene (nt 49-108) and followed by a FLAG epitope tag coding sequence. Upstream of, andin frame with, the coding sequence is the nearly ubiquitously expressed promoter of the H2-Dd major histocompatibility class I gene, and downstream of and out of frame with it is the 3' end of the human growth hormone gene. RT-PCR and immunoblot analysis for the FLAG epitope detected high levels of mRNA and protein, respectively, in numerous tissues. Whereas IL15 is undetectable in sera of wild-type mice, measurable levels are present in ~75% of transgenic sera. [MGI Ref ID J:67478]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(H2-D-Il15)3304Clgr, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Additional References

Tg(H2-D-Il15)3304Clgr related

Fehniger TA; Suzuki K; Ponnappan A; VanDeusen JB; Cooper MA; Florea SM; Freud AG; Robinson ML; Durbin J; Caligiuri MA. 2001. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193(2):219-31. [PubMed: 11208862]  [MGI Ref ID J:67478]

Fehniger TA; Suzuki K; VanDeusen JB; Cooper MA; Freud AG; Caligiuri MA. 2001. Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis 27(1):223-30. [PubMed: 11358383]  [MGI Ref ID J:69192]

French AR; Kim S; Fehniger TA; Pratt JR; Yang L; Song YJ; Caligiuri MA; Yokoyama WM. 2007. Chronic lymphocytosis of functionally immature natural killer cells. J Allergy Clin Immunol 120(4):924-31. [PubMed: 17604094]  [MGI Ref ID J:137640]

Richards JO; Chang X; Blaser BW; Caligiuri MA; Zheng P; Liu Y. 2006. Tumor growth impedes natural-killer-cell maturation in the bone marrow. Blood 108(1):246-52. [PubMed: 16556890]  [MGI Ref ID J:135679]

Sunwoo JB; Kim S; Yang L; Naik T; Higuchi DA; Rubenstein JL; Yokoyama WM. 2008. Distal-less homeobox transcription factors regulate development and maturation of natural killer cells. Proc Natl Acad Sci U S A 105(31):10877-82. [PubMed: 18664585]  [MGI Ref ID J:139949]

Yu L; Liu C; Vandeusen J; Becknell B; Dai Z; Wu YZ; Raval A; Liu TH; Ding W; Mao C; Liu S; Smith LT; Lee S; Rassenti L; Marcucci G; Byrd J; Caligiuri MA; Plass C. 2005. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 37(3):265-74. [PubMed: 15723065]  [MGI Ref ID J:97873]

Zhao H; Nguyen H; Kang J. 2005. Interleukin 15 controls the generation of the restricted T cell receptor repertoire of gamma delta intestinal intraepithelial lymphocytes. Nat Immunol 6(12):1263-71. [PubMed: 16273100]  [MGI Ref ID J:112655]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as hemizygotes. The donating investigator reports that homozygous mice may be infertile, and carrier males may be hard to breed after 8 weeks of age. In addition, carrier mice can often be identified by early hair thinning, especially around the ears.
Mating System	+/+ sibling x Hemizygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-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.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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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