These double mutant mice uniquely express human HLA-A2.1.
Dr. David Serreze, The Jackson Laboratory
Genetic Background | Generation |
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|
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | B2m | beta-2 microglobulin |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
NOD mice carrying only the HLA-A/H2-D/B2M transgene, commonly referred to as NOD.HHD, (Stock No. 006604) develop significantly accelerated diabetes onset compared to NOD/ShiLtDvs (NOD) inbred mice.
This mutant stock is also homozygous for the B2mtm1Unc mutation which normally prevents the development of of CD8+ T cells. The presence of the transgene in the B2m-deficient background, however, restores CD8+ T cells, but at a significantly lower level than in NOD inbred mice. Due to the covalently linked nature of the B2M component encoded into the transgene, the transgenic construct is unable to rescue murine MHC class 1 molecules in the NOD.B2m deficient (Stock No. 002309) mice. Thus, these double mutant mice only express human HLA-A2.1. Fifty-five percent of these NOD transgenic B2m-deficient mice develop diabetes by 30 weeks of age, while non-transgenic NOD.B2mtm1Unc do not develop diabetes. Insulitis scores assessed via histological examination of pancreata are similar between NOD/ShiLtDvs and NOD transgenic B2m-deficient mice. Although CD8+ T cell numbers in NOD transgenic B2m-deficient are lower than in NOD inbred mice, comparable numbers of CD8+ T cells can be cultured from pancreatic islets from both strains. The infiltrating T cells cultured from the double mutant islets are HLA-A2.1-specific, and are able to recognize islet specific antigens, such as IGRP.
NOD transgenic mice carrying the Prkdcscid (Stock No. 006605) do not become diabetic.
This model provides humanized T cells that will be useful tools to identify MHC class I epitopes recognized by CD8+ T cells in type 1 diabetes patients and for testing new therapies focused on restoring immune tolerance.
This transgene encodes a human B2-microglubulin (B2M) covalently linked to the MHC class 1, alpha1 and alpha2 binding domains of the human HLA-A2.1 gene and the alpha3, cytoplasmic and transmembrane domains of the murine H2-Db. The transgene was injected into NOD/ShiLtDvs embryos. In 2007, the T1DR received this Stock No. 006604 - NOD/ShiLtDvs-Tg(HLA-A/H2-D/B2M)1Dvs/J at generation N1F15. Stock No. 006604 was crossed to Stock No. 002309 - NOD.129P2(B6)-B2mtm1Unc/J. The resulting offspring were sibling mated to provide double mutant HLA transgenic, B2m deficient mice.
Expressed Gene | B2M, beta-2-microglobulin, human |
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Expressed Gene | HLA-A, major histocompatibility complex, class I, A, human |
Site of Expression |
Allele Name | targeted mutation 1, University of North Carolina |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | b2mnull; beta2M-; beta2m0; beta2mnull; beta2mo; beta2mtm1Unc; beta2MKO; beta2-m-KO; I0; MHC-I- |
Gene Symbol and Name | B2m, beta-2 microglobulin |
Gene Synonym(s) | |
Strain of Origin | 129P2/OlaHsd |
Chromosome | 2 |
Molecular Note | Insertion of a neomycin-resistance gene into the second exon. |
Mutations Made By | Dr. Oliver Smithies, University of North Carolina at Chapel Hill |
Allele Name | transgene insertion 1, David Serreze |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | HDD; HHD |
Gene Symbol and Name | Tg(HLA-A/H2-D/B2M)1Dvs, transgene insertion 1, David Serreze |
Gene Synonym(s) | |
Promoter | HLA-A2.1, major histocompatibility complex, class I, subtype A2.1, human |
Expressed Gene | B2M, beta-2-microglobulin, human |
Expressed Gene | HLA-A, major histocompatibility complex, class I, A, human |
Strain of Origin | NOD/ShiLtDvs |
Chromosome | UN |
General Note | The HDD construct was created and used to generate a differnet transgenic mouse line in J:41077. |
Molecular Note | This transgene encodes a human B2-microglubulin (B2M) covalently linked to the MHC class 1, alpha1 and alpha2 binding domains of the human HLA-A2.1 gene, and the alpha3, cytoplasmic and transmembrane domains of the murine H2-Db. The construct was injected into fertilized NOD/ShiLtDvs oocytes. The construct was originally described in J:41077 and used to create a different transgenic line. |
Mutations Made By | Dr. David Serreze, The Jackson Laboratory |
When maintaining a live colony, female mice heterozygous for the B2mtm1Unc allele and homozygous for the transgene can be bred to males homozygous for the B2mtm1Unc allele and transgene.
When using the NOD.B2mnull, HHD mouse strain in a publication, please cite the originating article(s) and include JAX stock #006611 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Heterozygous or Homozygous for B2m<tm1Unc>, Hemizygous or Homozygous for Tg(HLA-A/H2-D/B2M)1Dvs |
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