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

Abstract

PreTCRs use horizontal docking geometry The T cell receptor (TCR) recognizes peptide-bound major histocompatibility complex molecules (pMHCs) and consists of an α chain in association with a β chain. Both chains have hypervariable complementarity-determining regions (CDRs) that inform whether a particular TCR can recognize a given pMHC. To successfully graduate from the thymus, aspiring αβT cells must generate a functional TCR. During one early checkpoint in this process, the β chain is first paired with a preTβ chain to form the preTCR. Li et al. used x-ray crystallography to visualize how preTCRs recognize pMHCs. They report that the CDR3 loop of the preTCR β chain contacts the pMHC with a distinctive lateral topography. This is in contrast to the established binding modality of mature TCRs, whereby all three CDR loops on both α and β chains bind in a vertical orientation. These complexes help solve the mystery of how only functionally rearranged β chains using competent CDR3 loops can properly engage with pMHC at the preTCR stage. Science, this issue p. 181 A dynamic preTCR binding orientation fosters major histocompatibility complex recognition and thymocyte development. 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.