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 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 V-alpha 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.