Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC

The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCRαβ/CD3δγε2ζ2 complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements. [Display omitted] •Connecting peptides create rigid links to stabilize membrane-bound TCR subunits•Sterol lipid contributes to transmembrane assembly of the TCR complex•A pMHC/TCR structure highlights the cooperative nature of antigen recognition•TCR signaling may be triggered without spontaneous structural rearrangements Cryo-EM structural analysis of a T cell receptor (TCR) complex bound to a tumor-specific human class I pMHC indicates the functional impact of connecting peptides and sterol lipid for complex assembly and suggests that TCR signaling may be triggered without spontaneous structural rearrangements.