Dataset Information

Key Residues at Third CDR3? Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs.

ABSTRACT: The human invariant NK (iNK) TCR is largely composed of the invariant TCR V?24-J?18 chain and semivariant TCR V?11 chains with variable CDR3? sequences. The direct role of CDR3? in Ag recognition has been studied extensively. Although it was noted that CDR3? can interact with CDR3?, how this interaction might indirectly influence Ag recognition is not fully elucidated. We observed that the third position of V?11 CDR3 can encode an Arg or Ser residue as a result of somatic rearrangement. Clonotypic analysis of the two iNK TCR types with a single amino acid substitution revealed that the staining intensity by anti-V?24 Abs depends on whether Ser or Arg is encoded. When stained with an anti-V?24-J?18 Ab, human primary invariant NKT cells could be divided into V?24 low- and high-intensity subsets, and Arg-encoding TCR V?11 chains were more frequently isolated from the V?24 low-intensity subpopulation compared with the V?24 high-intensity subpopulation. The Arg/Ser substitution also influenced Ag recognition as determined by CD1d multimer staining and CD1d-restricted functional responses. Importantly, in silico modeling validated that this Ser-to-Arg mutation could alter the structure of the CDR3? loop, as well as the CDR3? loop. Collectively, these results indicate that the Arg/Ser encoded at the third CDR3? residue can effectively modulate the overall structure of, and Ag recognition by, human iNK TCRs.

SUBMITTER: Chamoto K

PROVIDER: S-EPMC5262525 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Key Residues at Third CDR3β Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs.

Chamoto Kenji K Guo Tingxi T Scally Stephen W SW Kagoya Yuki Y Anczurowski Mark M Wang Chung-Hsi CH Rahman Muhammed A MA Saso Kayoko K Butler Marcus O MO Chiu Priscilla P L PP Julien Jean-Philippe JP Hirano Naoto N

Journal of immunology (Baltimore, Md. : 1950) 20161221 3

The human invariant NK (iNK) TCR is largely composed of the invariant TCR Vα24-Jα18 chain and semivariant TCR Vβ11 chains with variable CDR3β sequences. The direct role of CDR3β in Ag recognition has been studied extensively. Although it was noted that CDR3β can interact with CDR3α, how this interaction might indirectly influence Ag recognition is not fully elucidated. We observed that the third position of Vβ11 CDR3 can encode an Arg or Ser residue as a result of somatic rearrangement. Clonotyp ...[more]

PMID: 28003379

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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

Key Residues at Third CDR3? Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs.

Publications

Key Residues at Third CDR3β Position Impact Structure and Antigen Recognition of Human Invariant NK TCRs.

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