B6.Cg-Immp2l^{Tg(HLA-A/H2-D)2Enge}/J

Stock number: 004191
Product name: AAD
Research areas: Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

AAD transgenic mice express an interspecies hybrid class I MHC gene, AAD, which contains the alpha-1 and alpha-2 domains of the human HLA-A2.1 gene and the alpha-3 transmembrane and cytoplasmic domains of the mouse H-2D^d gene/allele, under the direction of the human HLA-A2.1 promoter. This transgenic strain enables the modeling of human T cell immune responses to HLA-A2 presented antigens, and may be useful in testing of vaccines for infectious diseases or cancer therapy.

Goodwin et al. 2019 Genome Res 29:494 revealed that founder line 2 has more than five copies of the transgene integrated into the IMP2 inner mitochondrial membrane peptidase-like (S. cerevisiae) gene (Immp2l) on chromosome 12, causing a 1270 bp deletion and creating an Immp2l null allele.

Detailed description

AAD transgenic mice express an interspecies hybrid class I MHC gene, AAD, which contains the alpha-1 and alpha-2 domains of the human HLA-A2.1 gene and the alpha-3 transmembrane and cytoplasmic domains of the mouse H-2D^d gene/allele, under the direction of the human HLA-A2.1 promoter.

Goodwin et al. 2019 Genome Res 29:494 revealed that founder line 2 has more than five copies of the transgene integrated into the IMP2 inner mitochondrial membrane peptidase-like (S. cerevisiae) gene (Immp2l) on chromosome 12, causing a 1270 bp deletion and creating an Immp2l null allele.

Immunodetection of the HLA-A2.1 recombinant transgene established that expression was at equivalent levels to endogenous mouse class I molecules. The mouse alpha-3 domain expression enhances the immune response in this system. Compared to unmodified HLA-A2.1, the chimeric HLA-A2.1/ MHC Class I molecule mediates efficient positive selection of mouse T cells to provide a more complete T cell repertoire capable of recognizing peptides presented by HLA-A2.1 Class I molecules. The peptide epitopes presented and recognized by mouse T cells in the context of the HLA-A2.1/H2-D^d class I molecule are the same as those presented in HLA-A2.1⁺ humans. Mice homozygous for the transgenic insert are viable. Although the Donating Investigator reports that homozygotes are fertile, our experience here at The Jackson Laboratory has shown that breeding homozygous mice together results in reduced litters sizes and reduced colony productivity.

Hemizygous AAD transgenic mice exhibit HLA‐A2 expression in peripheral blood and spleen [view data; June 2020].

This AAD transgenic strain enables the modeling of human T cell immune responses to HLA-A2-presented antigens, and identification of those antigens. This transgenic strain is an important preclinical model for design and testing of vaccines for infectious diseases or cancer therapy involving optimal stimulation of CD8⁺ cytolytic T cells.

Development

A transgenic construct containing the leader, alpha-1 and alpha-2 domains of human HLA-A2.1 and the alpha-3 transmembrane and cytoplasmic domains of mouse H-2D^d was injected into fertilized (C57BL/6 X CBA/Ca)F1 mouse eggs. Founder animals were bred with C57BL/6 mice and backcrossed to C57BL/6 for at least 10 generations. See SNP note below.

In 2016, SNP (single nucleotide polymorphism) analysis performed by The Jackson Laboratory revealed that the Donating Investigator used C57BL/6N (2 of 5 markers segregating) in the development of the strain. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J at least once to establish the colony.

In Goodwin et al. 2019 Genome Res 29:494, it was discovered that founder line 2 has more than five transgene copies integrated into the IMP2 inner mitochondrial membrane peptidase-like (S. cerevisiae) gene (Immp2l) on chromosome 12 - causing a 1270 bp deletion and creating an Immp2l null allele.

Allele

Symbol: Immp2l^{Tg(HLA-A/H2-D)2Enge}
Name: transgene insertion 2, Victor H Engelhard
MGI accession ID: MGI:2153986
Generation method: Transgenic
Attributes: Null/Knockout; Inserted expressed sequence; Humanized sequence
Marker symbol: Immp2l
Marker name: IMP2 inner mitochondrial membrane peptidase-like (S. cerevisiae)
Chromosome: 12
Strain of origin: (C57BL/6 x CBA/Ca)F1
Expressed genes: HLA-A,major histocompatibility complex, class I, A,human
Molecular note: Transgenic mice express an interspecies hybrid class I MHC gene, AAD, which contains the alpha-1 and alpha-2 domains of the human HLA-A2.1 gene and the alpha-3 transmembrane and cytoplasmic domains of the murine H-2D gene, under the direction of the human HLA-A2.1 promoter. Immunodetection of the HLA-A2.1 recombinant transgene established that expression was at equivalent levels to endogenous murine class I molecules and to similar transgenic strains. Line 2 inserted into the gene at 41759331-41760601 (Build GRCm38/mm10) resulting in a 1270 bp deletion. The deletion results in a functional knock-out. Founder line 2 has a copy number of greater than 5.