Basic Information
Description
CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152, competitively binds to B7-1 (CD80) and B7-2 (CD86) on Antigen-Presenting Cells (APCs) to block the T cell activating signal by B7 and CD28 (on T cells) interaction. The inhibition of CTLA4 by its inhibitory antibodies enhances T cell activity. The CTLA4 antibody is the first FDA-approved antibody to treat advanced melanoma.
TNFRSF9 (Tumor necrosis factor receptor super family, member 9), also called CD137 and 4-1BB, is a co-stimulatory molecule and is mainly expressed on the surface of T, NK and mononuclear cells. CD137 is activated by its ligand CD137L or activating anti-CD137 antibodies, resulting in T Cell Activation, proliferation and cytokine production. CD137L is expressed on antigen presenting cells such as dendritic cells and macrophages and activated B cells. In vivo studies show that CD137 activation increases anti-tumor immune responses, providing a new target for immunotherapy.
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Targeting Strategy
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Gene targeting strategy for B-hCTLA4/h4-1BB mice.
The exon 2 of mouse Ctla4 gene that encode the IgV domain were replaced by human CTLA4 exon 2 in B-hCTLA4/h4-1BB mice. The exons 2-7 of mouse 4-1BB gene that encode the extracellular domain were replaced by human 4-1BB exons 2-7 in B-hCTLA4/h4-1BB mice.
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Details
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Phenotype
Protein Expression Analysis
Strain specific 4-1BB expression analysis in homozygous B-hCTLA4/h4-1BB mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hCTLA4/h4-1BB (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-h4-1BB antibody. Mouse 4-1BB was detectable in WT mice but not homozygous B-hCTLA4/h4-1BB mice. Human 4-1BB was exclusively detectable in homozygous B-hCTLA4/h4-1BB mice but not WT mice.
Strain specific CTLA4 expression analysis in homozygous B-hCTLA4/h4-1BB mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hCTLA4/h4-1BB (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-hCTLA4 antibody. Mouse CTLA4 was detectable in WT mice but not homozygous B-hCTLA4/h4-1BB mice. Human CTLA4 was exclusively detectable in homozygous B-hCTLA4/h4-1BB mice but not WT mice.
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References
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- J Immunol.1991 Aug 1;147(3):1037-44.
- J Exp Med.1991 Sep 1;174(3):561-9.
- PLoS One. 2014 Jan 21;9(1): e86337.
- Cancer Gene Ther. 2004 Mar;11(3):215-26.
