Small molecule inhibition of Csk alters affinity recognition by T cells
| Autor: | Boryana N. Manz, Ed Palmer, Kevan M. Shokat, Arthur Weiss, Adam H. Courtney, Ying Xim Tan, Florentine U. Rutaganira |
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| Rok vydání: | 2015 |
| Předmět: |
QH301-705.5
receptor Science T cell T-Lymphocytes Immunology Receptors Antigen T-Cell receptors Biology lymphocyte General Biochemistry Genetics and Molecular Biology immunology CSK Tyrosine-Protein Kinase chemistry.chemical_compound Mice cell biology medicine Cytotoxic T cell Animals Biology (General) Enzyme Inhibitors mouse Cell Proliferation Tyrosine-protein kinase CSK General Immunology and Microbiology General Neuroscience ZAP70 T-cell receptor tyrosine phosphorylation Tyrosine phosphorylation Cell Biology General Medicine T-Cell 3. Good health Cell biology medicine.anatomical_structure src-Family Kinases chemistry Antigen Medicine Src kinase Biochemistry and Cell Biology Signal transduction Src kinases signal transduction Research Article Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | eLife, vol 4, iss AUGUST2015 Manz, BN; Tan, YX; Courtney, AH; Rutaganira, F; Palmer, E; Shokat, KM; et al.(2015). Small molecule inhibition of Csk alters affinity recognition by T cells. eLife, 4(AUGUST2015). doi: 10.7554/eLife.08088. UCSF: Retrieved from: http://www.escholarship.org/uc/item/95p5m15s eLife eLife, Vol 4 (2015) |
| DOI: | 10.7554/eLife.08088. |
| Popis: | The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinases (SFK), plays a crucial role in controlling basal and inducible receptor signaling. To investigate how Csk activity regulates T cell antigen receptor (TCR) signaling, we utilized a mouse expressing mutated Csk (CskAS) whose catalytic activity is specifically and rapidly inhibited by a small molecule. Inhibition of CskAS during TCR stimulation led to stronger and more prolonged TCR signaling and to increased proliferation. Inhibition of CskAS enhanced activation by weak but strictly cognate agonists. Titration of Csk inhibition revealed that a very small increase in SFK activity was sufficient to potentiate T cell responses to weak agonists. Csk plays an important role, not only in basal signaling, but also in setting the TCR signaling threshold and affinity recognition. DOI: http://dx.doi.org/10.7554/eLife.08088.001 eLife digest The immune system has ‘T’ cells that recognize when the body is infected with a virus or bacterium and mount an immune response that is targeted to that microbe. They can also find and eliminate cancer cells. The microbes and cancer cells produce molecules called antigens that are detected by proteins on the surface of the T cell called T cell receptors (TCR). Antigen recognition causes the TCRs to transmit signals to the inside of the T cell that trigger an immune response. The degree to which the TCRs are active, and the length of time that they transmit signals regulates the size of the immune response. Therefore, developing new drugs that manipulate the activity of TCRs could be useful to treat many diseases. An enzyme called Csk inhibits the activities of a small family of proteins involved in a variety of different processes. One protein that Csk targets is called Lck and is required for the activation of immune responses in T cells. However, it is not clear whether Csk interacting with this protein stops the release of signals from TCRs, or whether it alters the level to which TCRs need to be activated before they transmit the signals. Manz, Tan et al. studied T cells from mice that had a mutant form of Csk that is inhibited by a drug called 3-iodo-benzyl-PP1 (3-IB-PP1), but otherwise works normally. When these cells detected an antigen in the presence of the drug, its TCRs were more highly activated and transmitted signals for a longer period of time than cells not exposed to the drug. The drug especially enhanced immune responses to very weak antigens, ones that might not activate T cells under normal circumstances. Manz, Tan et al.'s findings confirm that Csk plays a negative role in the activation of T cells and suggest that Csk may be a useful target for drug therapies that aim to fine-tune immune responses. The next challenge is to find a drug that can inhibit normal Csk enzymes and test this in mice and other animals. DOI: http://dx.doi.org/10.7554/eLife.08088.002 |
| Databáze: | OpenAIRE |
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