NOD.Cg-Prkdc^scid Il2rg^tm1Wjl H2-Ab1^b-tm1Doi Tg(HLA-DRB1)31Dmz/SzJ

Stock number: 017637
Product name: NSG-Ab^o DR4
Strain synonyms: NOD-scid IL2rgamma AB^o Tg(HLA-DR4)
Research areas: Cancer Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

These compound mutant NSG-Ab^o DR4 mice lack expression of the murine Prkdc gene, the X-linked Il2rg gene, and MHC class II while expressing the human leukocyte antigen DR4 gene. These mice may be useful for targeting human CD4⁺ T cells in transplantation studies in the absence of xeno-GVHD.

To order this model with CD34+ or PBMC engraftment, please visit our Humanized Mice page.

Detailed description

These NSG-Ab^o DR4 mice lack expression of the murine Prkdc gene, the X-linked Il2rg gene, and MHC class II, but express the human leukocyte antigen DR4 gene. When maintained as homozygous for all three targeting events, and carrying one copy of the transgene, these mice are viable and fertile. Unlike in the NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice (Stock No. 005557), the expression of HLA-DR4 in these mice leads to the development of allo-graft-versus-host disease (GVHD) after engraftment of human DR4-negative CD4⁺ T cells. These mice may be useful for targeting human CD4⁺ T cells in transplantation studies in the absence of xeno-GVHD.

Development

NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/Sz mice (NSG; see Stock No. 005557) were bred to NOD^scid mice bearing the H2-Ab1 knock-out allele (Ab^o; see below). Male NSG-Ab^o mice, homozygous for all three targeted mutations, were then crossed to female NOD mice hemizygous for the HLA-DR4 (DRB1*0401) transgene (Tg(HLA-DRB1)31Dmz). These NSG-Ab^o DR4 mice are maintained as homozygous for all three targeting events, and hemizygous for the transgene.

The H2-Ab1 knock-out allele in Stock No. 017637 was originally reported to be H2-Ab1^b-tm1Gru (created by Dr. Michael J. Grusby; while at Harvard) - harboring a forward-oriented neomycin resistance cassette that disrupts H2-Ab1 exon 2 (and made in ES cells with a deletion in the promoter region of H2-Ea). In 2018, quality control efforts at The Jackson Laboratory were completed that revealed Stock No. 017637 instead has the very similar H2-Ab1^b-tm1Doi knock-out allele (created by Drs. Christophe Benoist and Diane Mathis; while at INSERM) - harboring a reverse-oriented neomycin resistance cassette that disrupts H2-Ab1 exon 2 (and made in ES cells with a deletion in the promoter region of H2-Ea).

 

Allele

Symbol: Tg(HLA-DRB1)31Dmz
Name: transgene insertion 31, Dennis M Zaller
MGI accession ID: MGI:3529465
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: DR4Dw4; DRB1*0401; HLA-DR4; HLA-DR4 (DRB1*0401)
Marker symbol: Tg(HLA-DRB1)31Dmz
Marker name: transgene insertion 31, Dennis M Zaller
Marker synonyms: DR4Dw4; DRB1*0401; HLA-DR4
Chromosome: UN
Strain of origin: (C57BL/6J x SJL/J)F2
Expressed genes: RBM45,RNA binding motif protein 45,human
Molecular note: A chimeric MHC class II complex was created by fusing the human peptide binding domains of class II alpha and beta chains to the CD4 binding domains of murine class II alpha or beta chains. The was done by the construction of two separate transgene constructs. The alpha1 and beta1 domains isolated from human DRB1*0401 (DR4Dw4) replaced the corresponding alpha1 (aa 1-85) and beta1 (aa 1-96) domains of the H2-Ea and H2-Eb1 genes that make up mouse I-E^d. The native murine promoters were left intact. These transgene constructs were co-injected into fertilized eggs. Flow cytometry analysis indicates that virtually all B-cells and macrophages co-express the chimeric MHC class II molecules. The MHC class II chimeric molecules can be physiologically regulated as there is a 3-4 fold increase in MHC II molecules when splenic B-cells are cultured overnight with IL-4.

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Synonyms: scid
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
Marker synonyms: DNAPDcs; DNAPK; DNA-PK; DNAPKc; DNA-PKC; DNA-PKcs; DNPK1; DOXNPH; dxnph; HYRC; HYRC1; IMD26; p350; S473K; slip; XRCC7
Chromosome: 16
Strain of origin: C.BKa-Igh^b/Icr
Site of expression: T and B lymphocytes.
Molecular note: A T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) created a premature stop codon (p.Y4046*).

Allele

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: [KO]gammac; CD132^-; gammac^-; gc^-; Il2rg^tm1Wjll; IL2Rgamma^null
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Marker synonyms: [g]c; Ab2-183; Cd132; CIDX; common cytokine receptor gamma chain; common gamma chain; gamma C receptor; gamma(c); gammaC; gc; IL-2RG; IMD4; P64; SCIDX; SCIDX1
Chromosome: X
Strain of origin: 129S4/SvJae
Site of expression: Primarily lymphoid cells.
Molecular note: A neomycin resistance cassette replaced part of exon 3 and all of exons 4 - 8 of the gene, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.

Allele

Symbol: H2-Ab1^b-tm1Doi
Name: targeted mutation 1, Christophe Benoist and Diane Mathis
MGI accession ID: MGI:1927483
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: A beta⁰; A^bbeta^-; AB0; Abeta-; Class II⁰; H2-Ab1^tm1Dim; H2-Ab1^tm1Doi; H2-Ab1tm1Doi; II⁰; MHC class II-; MHCII^-; MHC-II-k.o.
Marker symbol: H2-Ab1
Marker name: histocompatibility 2, class II antigen A, beta 1
Marker synonyms: A beta; Abeta; Bb; CELIAC1; DQB2; H-2Ab; H2-Ab; HLA-DQB; HLA-DQB1; HLA-DXB; I-A^b; Ia2; Ia-2; IAb; I-Abeta; IDDM1; Rmcs1; RT1.B
Chromosome: 17
Strain of origin: 129S2/SvPas
Molecular note: The second exon was disrupted by the insertion of a neomycin resistance gene. In addition, the ES cell line used was derived from the 129S2/SvPas strain, which carries a deletion in the promoter region of H2-Ea. Consequently, these MHC class II molecule-deficient mice lacked cell surface expression of both class II-A and class II-E MHC proteins.