FVB-Tg(H2-D-Il15)3304Clgr/J

Stock number: 006125
Product name: IL-15tg
Research areas: Cancer Research, Cardiovascular Research, Dermatology Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools

Description

IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes, and later develop fatal lymphocytic leukemia with a T-NK phenotype. Progressive alopecia is seen as early as 5-6 weeks of age, with skin lesions appearing over time.

Detailed 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.

Allele

Symbol: Tg(H2-D-Il15)3304Clgr
Name: transgene insertion 3304, Michael A Caligiuri
MGI accession ID: MGI:3623278
Generation method: Transgenic
Attributes: Inserted expressed sequence
Marker symbol: Tg(H2-D-Il15)3304Clgr
Marker name: transgene insertion 3304, Michael A Caligiuri
Chromosome: UN
Strain of origin: FVB/N
Expressed genes: Il15,interleukin 15,mouse, laboratory
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, and in frame with, the coding sequence is the nearly ubiquitously expressed promoter of the H2-D^d 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.
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)