Human adaptive immune cells (T cells and B cells) play a key role in pathogenic infections, carcinogenesis, and autoimmune diseases. T and B cells recognize antigenic signals through T cell receptor (TCR) and B cell receptor (BCR), respectively, and transmit the signals across the membrane into the cell to activate the immune response of T and B cells. T and B cell receptors belong to a class of the most complex cell receptors composed of multiple proteins, which play a crucial role in the development, differentiation and function of T and B cells. The complex signal transduction, the structural basis and molecular mechanism of immune activation of TCR and BCR have always been an important basic scientific problem in immunology.

In recent years, in the study of the structure and molecular mechanism of human immune cell receptors, the Zhiwei Huang group first resolved the three-dimensional structure of human TCR complex by solving technical problems such as the dynamic complexity of TCR and BCR complex, and revealed the subunit assembly and recognition mechanism of TCR complex (Nature, 2019). Through further analysis of high-resolution TCR complex structure, the group found that there was a cholesterol binding channel in the transmembrane region of TCR (Molecular Cell, 2022). Cholesterol molecules bind to this channel to inhibit TCR activation, and the structural basis of TCR activation is revealed by removing cholesterol molecules to cause TCR constitutive activation. Thus, the cholesterol - deadbolt control theory of TCR is proposed, which provides a theoretical basis for rational design of immunotherapy targeting TCR to regulate T cell activity.

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http://doi.org/10.1126/science.abo3828