Structural Basis of Plasticity in T Cell Receptor Recognition of a Self Peptide-MHC Antigen

TLDR

T cell receptors possess dual specificity, enabling thymic self‑antigen recognition during maturation while discriminating foreign pathogens in the periphery. The crystal structure of the alloreactive 2C TCR bound to the self peptide–MHC H‑2K^b–dEV8 shows poor shape complementarity, minimal peptide contact, and large CDR loop rearrangements that together provide structural plasticity allowing the Vα‑mediated orientation to scan diverse peptides for kinetic stabilization of signaling.

Abstract

The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C TCR bound to self peptide–major histocompatibility complex (pMHC) antigen H-2K b –dEV8 refined against anisotropic 3.0 angstrom resolution x-ray data. The interface between peptide and TCR exhibits extremely poor shape complementarity, and the TCR β chain complementarity-determining region 3 (CDR3) has minimal interaction with the dEV8 peptide. Large conformational changes in three of the TCR CDR loops are induced upon binding, providing a mechanism of structural plasticity to accommodate a variety of different peptide antigens. Extensive TCR interaction with the pMHC α helices suggests a generalized orientation that is mediated by the V α domain of the TCR and rationalizes how TCRs can effectively “scan” different peptides bound within a large, low-affinity MHC structural framework for those that provide the slight additional kinetic stabilization required for signaling.