Billions of cells are turned over every day in human body through apoptosis or killed by pathological infections and inflammation. Dead cells have to be removed by immune system to avoid various problems, for example, autoimmune diseases. Phagocytes such as dendritic cells and macrophages can engulf dead cells by recognizing specific markers on these cells through surface receptors.
In a paper published recently in the Proceedings of the National Academy of Sciences USA, scientists from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, find that a dendritic cell receptor, called DEC205 or CD205, has a unusual property in recognizing dead cells. DEC205 is one of the major endocytotic receptors on dendritic cells and has been widely used as a receptor target in immune therapies for vaccine generation against tumors and viruses. However, both the structure and the functional mechanism of DEC205 remain unclear.
In this research, people from Prof. HE Yongning’s group determine the three-dimensional structure of the extra-cellular part of DEC205 using cryo-electron microscopy 3D reconstruction, a structural technique that has shown great potential in macromolecular structural determination in recent years. The results show that DEC205 undergoes a dramatic conformational change between acidic and basic environments. In acidic environment, DEC205 forms a compact double-ring shaped conformation, and when environment pH shifts from acidic to basic, the double-ring shape of DEC205 will open and adopts an extended conformation. Furthermore, researchers find that the conformational change of DEC205 at different pH is correlated with its ligand binding and release. DEC205 only recognizes apoptotic and necrotic cells at acidic pH, but not at basic pH. In contrast, DEC205 does not recognize healthy cells at either acidic or basic environment. Up to date, a number of phagocyte receptors have been identified to be involved in removing apoptotic and necrotic cells, but none of these receptors has shown the pH-dependent activities so far. Therefore this novel activity of DEC205 suggests that it mediates a new pathway for immune clearance of dead cells.
It is known that acidosis is commonly associated with apoptosis, tumorigenesis and inflammation. For example, tumor cells usually have higher intracellular pH and lower extracellular pH. Thus the pH-dependent activity of DEC205 may give it an advantage to recognize tumors specifically for clearance. Since DEC205 has already been used in vaccine generation against various antigens, the finding in this research may provide more potential for immune therapies against tumors.
This research entitled “pH-dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205”is published on line before print on May 26, 2015. It is supported by the grands from Chinese Academy of Sciences, National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.
CONTACT:
HE Yongning, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai, China
E-mail:he@sibcb.ac.cn
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