Human T cells are expressed by both coinhibitory (e.g. cytotoxic T lymphocyte-associated antigen 4 [hCTLA-4] ) and costimulatory receptor (e.g. hCD137) ). Blocking the hCTLA-4 and stimulating the hCD137 could enhance the anti-tumor immunity, which has been recognized as a novel therapy for cancer patients. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hCTLA-4/hCD137 dual humanized mice for our clients all over the world.
hCTLA-4, also known as CD152, is a leukocyte differentiation antigen and a transmembrane receptor on T cells. hCTLA-4, as a class of membrane protein, has only 36 amino acids at the intracellular end. This part of the amino acid sequence constitutes a type called immune tyrosine inhibitory motif (ITIM), which is opposite to the hCD28 intracellular immune tyrosine activating motif (ITAM). Both hCTLA-4 and hCD28 molecules are members of the immunoglobulin superfamily (IgSF) and share a high degree of homology. hCTLA-4 presents on activated CD4+ and CD8+ T cells, and its natural ligands are B7 molecules, including CD80 and CD86 molecules. The affinity of hCTLA-4 for B7 is significantly higher than that of hCD28 molecule.
hCD137 is also called 4-1BB, and the ligand for hCD137 is hCD137L. hCD137 belongs to the tumor necrosis factor receptor superfamily (TNFRSF) and is encoded by the gene of tumor necrosis factor receptor superfamily member 9 (TNFRSF9). hCD137 is a type II transmembrane protein presenting on cell membrane with a full length of 255aa (17aa signal peptide, 169aa extracellular region, 27aa transmembrane region, and 42aa intracellular region). Its extracellular region has abundant cysteines, and the intracellular region contains a 5aa conserved sequence. hCD137 is an inducible costimulatory receptor expressed on activated CD4+ and CD8+ T cells, natural killer cells (NKs), dendritic cells (DCs), macrophages, eosinophils, neutrophils, mast cells, and regulatory T cells (Tregs).
The cytoplasmic region of the hCTLA-4 molecule has an immunoreceptor tyrosine inhibitory motif. After being phosphorylated, the tyrosine residue in ITIM can be combined with protein tyrosine phosphatase (SHP-1) and inositol 5-phosphatase (SHIP) to transmit inhibitory signals which can prevent the activation and proliferation of T cells and reduce the differentiation of memory T cells. As an important pair of costimulatory molecules, hCD137/hCD137L regulates T cell-mediated immune response by transmitting activation, proliferation, or apoptosis signals between immune cells. hCD137 signal transduction can stimulate the proliferation of NKs and T cells and produce anti-tumor activity. hCD28 is down-regulated by the negative feedback receptor hCTLA-4. The hCD137 on T cells triggered by hCD137L on the surface of antigen-presenting cells (APCs) provides a costimulatory signal, which can maintain B7: CD28-mediated cell activation and further enhance the proliferation and survival ability of CD8+ T cells. In CD4+ T cells, hCD137/hCD137L signaling can induce cell expansion.
Fig.1 CTLA-4 pathway and CD137 pathway in T cell activation. (Cheuk, 2004)
Monotherapy blocking the hCTLA-4 pathway is unlikely to restore an effective T cell response and have an optimal response rate in cancer patients. The combinational therapy of anti-hCTLA-4 antibody and anti-hCD137 agonist antibody will promote the immune activity and has been investigated in clinical trials. With advanced technology, Creative Biolabs has multiple well-established Magic™ “humanized” animal models, including the hCTLA-4/hCD137 dual humanized mice for different research purposes. If you have any questions about these humanize mice, please feel free to contact us for more details. Our scientists will work closely with you and assist you in your study project.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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