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Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155.

ABSTRACT: During normal T cell development in the thymus, ?? TCRs signal immature thymocytes to differentiate into mature T cells by binding to peptide-MHC ligands together with CD4/CD8 coreceptors. Conversely, in MHC and CD4/CD8 coreceptor-deficient mice, the thymus generates mature T cells expressing MHC-independent TCRs that recognize native conformational epitopes rather than linear antigenic-peptides presented by MHC. To date, no structural information of MHC-independent TCRs is available, and their structural recognition of non-MHC ligand remains unknown. To our knowledge in this study, we determined the first structures of two murine MHC-independent TCRs (A11 and B12A) that bind with high nanomolar affinities to mouse adhesion receptor CD155. Solution binding demonstrated the V??-domain is responsible for MHC-independent B12A recognition of its ligand. Analysis of A11 and B12A sequences against various MHC-restricted and -independent TCR sequence repertoires showed that individual V-genes of A11 and B12A did not exhibit preference against MHC-restriction. Likewise, CDR3 alone did not discriminate against MHC binding, suggesting VDJ recombination together with V?/V? pairing determine their MHC-independent specificity for CD155. The structures of A11 and B12A TCR are nearly identical to those of MHC-restricted TCR, including the conformations of CDR1 and 2. Mutational analysis, together with negative-staining electron microscopy images, showed that the CDR regions of A11 and B12A recognized epitopes on D1 domain of CD155, a region also involved in CD155 binding to poliovirus and Tactile in human. Taken together, MHC-independent TCRs adopt canonical TCR structures to recognize native Ags, highlighting the importance of thymic selection in determining TCR ligand specificity.

SUBMITTER: Lu J

PROVIDER: S-EPMC7390066 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155.

Lu Jinghua J Van Laethem François F Saba Ingrid I Chu Jonathan J Tikhonova Anastasia N AN Bhattacharya Abhisek A Singer Alfred A Sun Peter D PD

Journal of immunology (Baltimore, Md. : 1950) 20200422 12

During normal T cell development in the thymus, αβ TCRs signal immature thymocytes to differentiate into mature T cells by binding to peptide-MHC ligands together with CD4/CD8 coreceptors. Conversely, in MHC and CD4/CD8 coreceptor-deficient mice, the thymus generates mature T cells expressing MHC-independent TCRs that recognize native conformational epitopes rather than linear antigenic-peptides presented by MHC. To date, no structural information of MHC-independent TCRs is available, and their ...[more]

PMID: 32321756

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Project description: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?1 segment can be rearranged with D?-J?-C? or J?-C? segments to form classical ??TCRs or uncommon ??TCRs using a V?1 segment (?/??TCR). Here we have determined two complex structures of the ?/??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 ??TCRs but display a strong tilt binding geometry of the V?1 domain toward the HLA ?1 helix, due to a conserved extensive interaction between the CDR1? loop and the N-terminal region of the ?1 helix (mainly in position 62). The aromatic amino acids of the CDR1? 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? loop could affect the extent of tilt binding of the V?1 domain, and adaptively, the pairing V? 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 ?? T cell recognition is determined by the CDR loops of the ??TCR, and the general mode of binding of ??TCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR ?/? chain locus, some V? segments can rearrange with the C? segment, forming a hybrid V?C?V?C? TCR, the ?/??TCR. However, the basis for the molecular recognition of such TCRs of their ligands is elusive. Here an ??TCR using the V?1 segment, S19-2, was isolated from an HIV-infected patient in an HLA-A*24:02-restricted manner. We then solved the crystal structures of the S19-2 TCR and another ?/??TCR, TU55, bound to their respective ligands, revealing a conserved V?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?1 segment to its ligand, virus-derived pHLA.

Dataset Information

Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155.

Publications

Structure of MHC-Independent TCRs and Their Recognition of Native Antigen CD155.

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