2009
DOI: 10.1016/j.immuni.2009.11.003
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T Cell Receptor Cross-reactivity Directed by Antigen-Dependent Tuning of Peptide-MHC Molecular Flexibility

Abstract: Summary Tell mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The αβ TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences betwee… Show more

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Cited by 170 publications
(256 citation statements)
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References 40 publications
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“…Further experimentation will be required to explore the role of Gln152 in restraining T-cell responses. Interestingly, a similar rearrangement of α2 interhelical residues of HLA-A2 was also noted in the crystal structure of a ternary complex HLA-A2/ peptide/TCR (32). The conformation of residues Ala150-Val152 was found to switch in the face of the same TCR depending on the identity of the antigenic peptide, highlighting a mechanism whereby the antigen tuned the dynamic properties of the MHC molecule, and ultimately of the TCR, and facilitated cross-reactivity.…”
Section: Discussionsupporting
confidence: 54%
“…Further experimentation will be required to explore the role of Gln152 in restraining T-cell responses. Interestingly, a similar rearrangement of α2 interhelical residues of HLA-A2 was also noted in the crystal structure of a ternary complex HLA-A2/ peptide/TCR (32). The conformation of residues Ala150-Val152 was found to switch in the face of the same TCR depending on the identity of the antigenic peptide, highlighting a mechanism whereby the antigen tuned the dynamic properties of the MHC molecule, and ultimately of the TCR, and facilitated cross-reactivity.…”
Section: Discussionsupporting
confidence: 54%
“…The authors thus attribute this striking example of degenerate recognition to an "induced fit mechanism of molecular mimicry." It seems, however, that the molecular mimicry in this case is a consequence of the cross-recognition rather then its cause (94). We comment later on how this observation may fit within a general proposed model.…”
Section: T-cell Specificitymentioning
confidence: 62%
“…Some kinetic studies are consistent with an induced fit process (101, 102), but others question it (95). TCR-pMHC interface complementarity may also be affected by changes in epitope configuration (90,92,94,99). There is generally less complementarity at the TCR-pMHC interface than between AgAb interfaces, in keeping with the substantially lower affinities of TCR-pMHC than Ag interactions with affinity-matured Abs (although not lower than Ag binding to preaffinity-matured Abs).…”
Section: T-cell Specificitymentioning
confidence: 92%
“…9). In one telling case, however, the conformation of the ␣2 helix of the human class I MHC protein HLA-A*0201 (HLA-A2) was shown to undergo a large reorganization upon binding of the A6 TCR (10). Notably, this reorganization is dependent on the peptide as it has not been observed upon recognition of other HLA-A2-presented peptides by the same TCR (11,12).…”
mentioning
confidence: 99%
“…Indeed, with HLA-A2, the mobility of the region that undergoes a structural change upon binding of the A6 TCR was shown to vary with different peptides (10). This may not be a unique observation as similar effects are believed to contribute to differential T cell recognition of native and modified MART-1 peptides (6), and MHC flexibility can be altered by micropolymorphisms (7,14,15).…”
mentioning
confidence: 99%