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Pre-T cell receptors topologically sample self-ligands during thymocyte β-selection


Li XXiaolong , Mizsei RRéka , Tan KKemin , Mallis RJRobert J , Duke-Cohan JSJonathan S , Akitsu AAoi , Tetteh PWPaul W , Dubey AAbhinav , Hwang WWonmuk , Wagner GGerhard , Lang MJMatthew J , Arthanari HHaribabu , Wang JHJia-Huai , Reinherz ELEllis L . Science (New York, N.Y.). 2020 12 17; 371(6525). 181-185


Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and αβTCRs. Using x-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to “horizontally” grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementarity-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in “vertical” head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide’s featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. “Horizontal” docking precludes germline CDR1β- and CDR2β-MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.