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

作者：K. Christopher García, Massimo Degano, Larry R. Pease, Mingdong Huang, Per A. Peterson, Luc Teyton, Ian A. Wilson · 发表于：Science · 年份：1998 · DOI：10.1126/science.279.5354.1166 · 被引用次数：689 · 研究领域：T-cell and B-cell Immunology、Immune Cell Function and Interaction、Monoclonal and Polyclonal Antibodies Research

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-2Kb-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 beta 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 alpha helices suggests a generalized orientation that is mediated by the Valpha 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.