Shapes of MHC Restriction Review structures of a TCR b subunit and a

face of the molecule. A fourth loop, termed HV4, is also † Molecular Immunology Section present. The exception to these similarities has been Neuroimmunology Branch the C domain of the ␣ chain that has a noncanonical National Institute of Neurological Disorders fold (Garcia et al., 1996; Ding et al., 1998). Structural and Stroke studies of entire ␣␤TCR molecules were slowed by the National Institutes of Health the inability to produce sufficient amounts of TCR pro-Bethesda, Maryland 20892 tein to analyze, but in the last three years, several X-ray structures of human and murine ␣␤TCRs complexed with peptides bound to MHC class I molecules have The defining component of antigen-specific recognition been determined. Two different human ␣␤TCRs were by T lymphocytes with ␣␤ T cell receptors (TCRs) is identified in CD8 ϩ cytotoxic T cell clones (A6 and B7) MHC restriction. The concept of MHC restriction was specific for the Tax 11–19 peptide (LLFGYPVYV) of hu-derived from experiments which showed that virus-spe-man T cell lymphotrophic virus type-1 (HTLV-I) pre-cific effector T cells could only lyse virus-infected target sented by HLA-A2 and were isolated from the peripheral cells that were of the same MHC haplotype as the ef-blood of HTLV-I-infected patients (Utz et al., 1996). The fector T cells (Zinkernagel and Doherty, 1974). Two mod-A6 and B7 ␣ and ␤ chains were individually expressed els were proposed to explain the mechanism by which in bacteria, then refolded and bound to soluble forms an uncharacterized TCR could be specific for both the of HLA-A2 complexed with the Tax peptide and crystal-foreign antigen (e.g., virus) and self-MHC molecules: (1) lized (Garboczi et al., 1996a, 1996b; Ding et al., 1998). " altered self, " in which a given MHC molecule was al-A murine ␣␤TCR was obtained from a CD8 ϩ cytotoxic tered in an undefined, specific way that could be recog-T cell clone (2C) that was derived from alloimmunization nized by a single TCR; and (2) " dual recognition, " in of H-2 b mice with H-2 d cells and was initially shown to which two distinct receptors independently recognized be specific for H-2L d (Kranz et al., 1984). The 2C TCR the foreign antigen and the self-MHC molecule. Two was subsequently shown to be able to recognize the subsequent discoveries favored the altered self hypoth-self-peptide dEV8 (EQYKFYSV) derived from a mito-esis. First, MHC molecules were found to be peptide-chondrial protein presented by H-2K b …