The T cell receptor (TCR) is one of the most complicated receptors in mammalian cells. Attracted by the complexity and functional importance of TCR, many groups have been studying TCR structure and triggering for decades using diverse biochemical and biophysical tools.
Recently, a review, entitled “structural understanding of T cell receptor triggering”, by the research group led by Dr. XU Chenqi at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, is published online at Cellular & Molecular Immunology. The review synthesizes the structural studies and discusses the relevance of the conformational change model in TCR triggering.
T cells play essential roles in the adaptive immune response against pathogens and cancer cells. T cells specifically recognize peptide antigens loaded on the major histocompatibility complex (peptide-MHC, pMHC) upon TCR activation. As an octamer complex, TCR comprises an antigen-binding subunit (TCRαβ) and three CD3 signaling subunits (CD3γε, CD3δε, and CD3ζζ). Engagement of TCRαβ with an antigen pMHC leads to tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in CD3 cytoplasmic domains, thus translating extracellular binding kinetics to intracellular signaling events. To explain the triggering mechanism of TCR, several models have been proposed, including but not limited to kinetic segregation, serial engagement, kinetic proofreading, and conformational change.
Recently, a signi？cant breakthrough was made in the TCR ？eld. Dong et al. reported a cryo-electron microscopy (cryo-EM) structure of a human TCR–CD3 complex in its unliganded state at 3.7 ？ resolution (Nature. 573 (7775): 546-552, 2019). As expected, the TCR-CD3 complex is assembled with a 1:1:1:1 stoichiometry of TCRαβ/ CD3γε/CD3δε/CD3ζζ. Whether conformational change plays an important role in the transmembrane signal transduction of TCR is thus brought into attention again.
In the review, we highlight the conformational changes that occur in the extracellular, transmembrane, and intracellular domains upon TCR triggering. Most results corroborate each other and are useful for revealing the mechanism of TCR triggering. Since lipids play essential roles in regulating TCR structure and function, studying the TCR-CD3 complex in a native membrane environment is warranted in future research. Moreover, T cell-based immunotherapies such as TCR-T and CAR-T can be further developed and applied in the clinic based on a better understanding of TCR triggering.
Prof. XU Chenqi serves as the corresponding author to design the framework and extensively revise the manuscript. XU Xinyi and LI Hua, a graduate student and an associate professor in the XU Lab, serve as co-first authors. The work was supported by grants from NSFC grants, CAS grants (Strategic Priority Research Program; Facility-based Open Research Program; Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation).
Reference:
https://rdcu.be/b1wik.
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