B6.Cg-Cd40^tm1Kik Tg(H2-Ea-Cd40/Pdlim7)#Bshp/BshpJ

Stock number: 039094
Product name: mCD40-LMP1tg
Research areas: Cancer Research, Immunology, Inflammation and Autoimmunity Research, Virology Research

Description

mCD40-LMP1Tg mice carry a knock-out of the mouse CD40 antigen (Cd40) gene and express, from the mouse MHC class II Eα (H2-Ea) promoter, a transgene composed of the external domain of mouse Cd40 and the cytoplasmic domain of the Epstein-Barr Virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) molecule. Mice express only the transgenic version of Cd40 in B cells, macrophages, and dendritic cells. Studies of LMP1 activity may be useful in studying the pathogenesis of EBV in humans.

Detailed description

mCD40-LMP1Tg mice carry a knock-out of the mouse CD40 antigen (Cd40) gene and express, from the mouse MHC class II Eα (H2-Ea) promoter, the external domain of mouse Cd40 and the cytoplasmic domain of the Epstein-Barr Virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) molecule. The H2-Ea promoter was selected because expression patterns for Cd40 and MHC class II largely overlap, allowing direct comparison of the functions of the cytoplasmic domains of CD40 versus its viral mimic, LMP1 in vivo. Mice express only the transgenic version of Cd40 in B cells, macrophages, and dendritic cells.

The mCD40-LMP1Tg mice have normal lymphyocyte subsets, and immunization elicits an antibody response featuring normal isotype switching, affinity maturation, and germinal center formation. The mCD40-LMP1tg mice have enlarged lymph nodes, hyperactive B cells and disordered tissue organization in secondary lymphoid structures. Unimmunized animals have expanded immature and germinal center B cells, produce autoantibodies, and exhibit marked splenomegaly and lymphadenopathy with elevated serum IL6 (as seen in human B cell lymphomas). This demonstrates that signaling through the LMP1 cytoplasmic tail results in amplified and abnormal mimicry of CD40 functions in vivo. These mice do not develop lymphomas over 2 years of observation (PMID:24605938; PMID:15308105). Studies of this activity by LMV1 may be useful in studying the pathogenesis of EBV in humans.

See Stock No. 039096 for the mCD40tg transgenic control strain that carries a knock-out of the mouse Cd40 gene and expresses full-length wildtype mouse Cd40 from the mouse MHC class II Eα (H2-Ea) promoter.

Development

The external domain of mouse Cd40 and the cytoplasmic domain of the Epstein-Barr Virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) molecule were isolated and placed under the control of the mouse MHC Class II Eα (H2-Ea) promoter. Two exons from rabbit β-globin were included to improve the efficiency of the transgene's mRNA processing. The transgenic vector was injected into B6SJLF2 embryos. Mice were backcrossed to C57BL/6NCr for 5-8 generations, then intercrossed with Cd40^tm1Kik (see Stock No. 002928) knock-out mice. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. Cryorecovery/live colony development will involve C57BL/6NJ (Stock No. 005304).

Allele

Symbol: Cd40^tm1Kik
Name: targeted mutation 1, Hitoshi Kikutani
MGI accession ID: MGI:1857457
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: CD40-; CD40 Ko; CD40KO; Tnfrsf5-; Tnfrsf5tm1Kik
Marker symbol: Cd40
Marker name: CD40 antigen
Marker synonyms: Bp50; CDW40; p50; Tnfrsf5
Chromosome: 2
Strain of origin: 129P2/OlaHsd
Molecular note: A neomycin cassette was inserted into exon 3. Disruption of the functionality of the protein was confirmed by a surface expression assay in spleen cells in which no binding of Tnfsf5 to ligand was observed.

Allele

Symbol: Tg(H2-Ea-Cd40/Pdlim7)#Bshp
Name: transgene insertion #, Gail Bishop
MGI accession ID: MGI:7569167
Generation method: Transgenic
Attributes: Inserted expressed sequence
Synonyms: mCD40-LMP1tg
Marker symbol: Tg(H2-Ea-Cd40/Pdlim7)#Bshp
Marker name: transgene insertion #, Gail Bishop
Chromosome: UN
Strain of origin: (C57BL/6 x SJL)F2
Molecular note: This transgene encodes a chimeric molecule consisting of the extracellular and transmembrane domains of mouse Cd40, and the cytoplasmic tail of Pdlim7 (mCD40-LMP1 in paper).Several lines were generated but were not distinguished.