Researchers from the La Jolla Institute of Allergy and Immunology have gained some new insights into the complex signaling pathways associated with T cell activation, the most important disease-resistant cell in the body, in an important study. The research findings were published in the famous scientific journal Nature in June 23rd. The team at the La Jolla Institute confirmed for the first time that a protein called septins plays a key role in activating calcium channels on the surface of T cells. This channel is the entrance of calcium ions from the blood into T cells, and its function is essential for the survival, activation and disease resistance of T cells.
Patrick Hogan and Anjana Rao are senior authors of this paper, and Sonia Sharma and Ariel Quintana are co-first authors of this paper. Dr. Hogan described this research discovery as an important step towards understanding the overall function of T cells-acquiring new knowledge about it will help to develop more precise targeted new drugs, treatments A large number of diseases ranging from cancer to emerging viral infections. “It ’s like operating an engine, you have to understand the role of all parts to repair it. We want to understand the basic device inside the T cells. This will allow us to target specific pressure points, thus improving the fight against tumors or viruses T cell response, or inhibit T cell response in the case of autoimmune diseases.
Dr. Sharma said: "We found that the septin protein very strongly regulates the calcium ion response, which is necessary for the activation of immune cells."
Dr. Hogan said the new research findings surprised the research team. "We used to know that septins existed in the plasma membrane of cells, but we didn't know that they were related to calcium ion signals." As we all know, Septins can build scaffolds to provide structural support during cell division.
The new study is based on a breakthrough research by Dr. Rao and Dr. Hogan in 2006: ORAI1 protein formed a calcium ion channel pore. As the gate of T cell function, the entrance of calcium channels is one of the hottest puzzles in biomedical science, and it is also of great significance for better understanding the mechanism by which the body uses these cells to fight diseases. The research team was surprised to find that septins formed a ring around calcium channels. "We are not sure why, but we think these septins rearrange the structure of the cell membrane, 'collecting together' the important proteins STIM and ORAI1, and possibly other proteins needed for the operation of calcium channels," said Dr. Hogan.
Dr. Sharma added: "We believe that these septins encode the interaction of these two proteins, which is essential for activating the immune response. Without septins involved, T cell activation will not occur." In this study, the study The staff devised a simple method to directly read the activity of a major signaling pathway leading to T cell activation (the clinical immunosuppressive drug ecomycin A is targeted to this signaling pathway), and detected when a single gene was knocked out. Activity damage. After sorting out about 20,000 human genes, 887 "hits" genes were found.
In further experiments, they will try to classify these hit genes to determine whether they are genes that affect calcium channels themselves or genes that subsequently play a role in the signaling pathway. "We hope that one or more of these genes can be used as clinical targets for new drugs to treat transplant rejection and immune diseases, as well as some of the same indications that are currently treated with cyclosporin A," said Dr. Hogan. He believes that the use of a drug treatment for the early steps of calcium influx through the ORAI channel may be more effective than cyclosporin A, and the side effects are smaller. Cyclosporine A targets a late step in the signaling pathway and can cause complications such as kidney disease.
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