Pre–T cell receptors topologically sample self-ligands during thymocyte β-selection
Xiaolong Li, Réka Mizsei, Kemin Tan, Robert J. Mallis, Jonathan S. Duke‐Cohan, Aoi Akitsu, Paul W. Tetteh, Abhinav Dubey, Wonmuk Hwang, Gerhard Wagner, Matthew J. Lang, Haribabu Arthanari, Jia‐Huai Wang, Ellis L. Reinherz
Abstract
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.