Conserved V Delta 1 Binding Geometry In A Setting Of Locus-Disparate Phla Recognition By Delta/Alpha Beta T Cell Receptors (Tcrs): Insight Into Recognition Of Hiv Peptides By Tcrs

Given the limited set of T cell receptor (TCR) V genes that are used to create TCRs that are reactive to different ligands, such as major histocompatibility complex (MHC) class I, MHC class II, and MHC-like proteins (for example, MIC molecules and CD1 molecules), the V delta 1 segment can be rearranged with D delta-J delta-C delta or J alpha-C alpha segments to form classical gamma delta TCRs or uncommon alpha beta TCRs using a V delta 1 segment (delta/alpha beta TCR). Here we have determined two complex structures of the delta/alpha beta TCRs (S19-2 and TU55) bound to different locus-disparate MHC class I molecules with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble those of classical gamma beta TCRs but display a strong tilt binding geometry of the V delta 1 domain toward the HLA alpha 1 helix, due to a conserved extensive interaction between the CDR1 delta loop and the N-terminal region of the alpha 1 helix (mainly in position 62). The aromatic amino acids of the CDR1 delta loop exploit different conformations ("aromatic ladder" or "aromatic hairpin") to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules and thus may potentially explain the nature of TCR cross-reactivity. In addition, the length of the CDR3 delta loop could affect the extent of tilt binding of the V delta 1 domain, and adaptively, the pairing V beta domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring TCR specificity for a certain peptide-MHC class I (pMHC-I). Our data have provided further structural insights into the TCR recognition of classical pMHC-I molecules, unifying cross-reactivity and specificity.IMPORTANCE The specificity of alpha beta T cell recognition is determined by the CDR loops of the alpha beta TCR, and the general mode of binding of alpha beta TCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR alpha/beta chain locus, some V delta segments can rearrange with the C alpha segment, forming a hybrid V delta C alpha V beta C beta TCR, the delta/alpha beta TCR. However, the basis for the molecular recognition of such TCRs of their ligands is elusive. Here an alpha beta TCR using the V delta 1 segment, S19-2, was isolated from an HIV-infected patient in an HLA-A*24:02-restricted man ner. We then solved the crystal structures of the S19-2 TCR and another delta/alpha beta TCR, TU55, bound to their respective ligands, revealing a conserved V delta 1 binding feature. Further binding kinetics analysis revealed that the S19-2 and TU55 TCRs bind pHLA very tightly and in a long-lasting manner. Our results illustrate the mode of binding of a TCR using the V delta 1 segment to its ligand, virus-derived pHLA.