T-cell is one of the important cells in human immune system. Understanding how T-cell recognizes the invasion of tumor cells, pathogens and other "enemy" is always the core of immunological research.Recently, Zhang Yonghui of Tsinghua University and Guo Ruiting of Hubei University revealed the mechanism of δ T T cell immune recognition in T cells.The major research results of the exemption were published in the international journal Nature on September 7.
T cells were divided into αβ T cells and δ T T cells.αβ T cell receptor (TCR) relies on MHC molecules on the surface of the target cell to recognize polypeptide antigens and detect the presence of "enemies".This concept establishes the theoretical foundation of many medical technologies.But since the early 1980s, δ T T cells have been found to play an important role in the development of tumors, infections and autoimmune diseases.Understanding the biological mechanism of δ T T cells is expected to expand the application of medical technology and break away from the traditional framework of αβ T cells.
In earlier studies, scientists found that tumors and pathogens could produce lipid metabolites called phosphine antigens, which activate the largest class of gamma- T T cells in the body's peripheral blood.But scientists wonder how these gamma- T T cells can detect phosphine antigens hidden inside the target cells.
In 2003, Zhang Yonghui began studying the chemical structure of phosphine antigens.In 2019, Yang Yunyun, a Ph.D. student from Zhang Yonghui's team, analyzed the crystals of phosphine antigen and BTN3A1 protein intracellular segment, confirming the importance of BTN3A1 in δ T T cell recognition.
"However, 受体对 T cell receptors are sensitive to tumor and pathogens, and the binding strength of phosphine antigen to BTN3A1 is far from sufficient to activate δ T T cells efficiently.Mr. Zhang introduced.In 2020, Yuan Linjie, another Ph.D. student from Zhang Yonghui's team, discovered that BTN3A1 had an "immunization partner" BTN2A1 in the process.The results, published in Nature, show how phosphine antigens, like "molecular glue," promote the tight binding of BTN3A1 and BTN2A1 in target cells.
"The natural phenomenon of 'molecular glue' has been discovered for more than 30 years, but is rarely associated with immunological surveillance.Our research demonstrates that this mechanism is a strategy for effective immune surveillance in the course of immune evolution.Zhang explains that the two proteins work together to capture phosphine antigens, thus enabling TδT cells to be "super" immune surveillance, even in small amounts of phosphine antigens present in tumors and pathogens.
So how do phosphine antigens cause BTN3A1 and BTN2A1 proteins to "stick" inside the target cells and transmit signals from inside to outside for δ T T cell receptors to perceive?
Phosphine antigens cross-linked the intracellular domains of BTN3A1 and BTN2A1 and induce epitope exposure in extracellular domains, thus binding to TCR effectively.
In order to analyze the molecular mechanism, the team adopted a series of experimental methods and concluded that BTN3A1 and BTN2A1 binding in the target cells induced exposure to the outer positions of BTN3A1 and BTN2A1 cells.
"In addition to primates, we have also captured the molecular glue behavior of phosphine antigens in the alpaca species, which is important for understanding the evolution of gamma- T T cells.Professor Guo Ruiting, another correspondent for the paper, added.
"This study reveals a rapid path to TCR-T cell therapy based on TδT cells, which can effectively identify and attack tumor cells and infectious cells by replacing phosphine antigens with a drug molecule."It's