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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 | 2017-01-01

REPOSITORIES: biostudies

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