Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide

Chan, Kok Fei; Gully, Benjamin S.; Gras, Stéphanie; Beringer, Dennis X.; Kjer‐Nielsen, Lars; Cebon, Jonathan; McCluskey, James; Chen, Weisan; Rossjohn, Jamie

doi:10.1038/s41467-018-03321-w

Cited by 46 publications

(39 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More dramatic peptide movements have been reported for binding of the ELS4 TCR to HLA-B*35:01-EPLPQGQLTAY, with a large shift of 5Å occurring in the center of the peptide [5]. Also, a recent study demonstrated that two different TCRs, recognizing the same HLA-B*07:02 restricted NY-ESO-1 peptide, could stabilize the peptide in very different conformations [53]. Our study adds to the story of flexibility during T-cell antigen recognition, through a TCR induced shift in peptide primary anchor residue usage.…”

Section: Discussionmentioning

confidence: 85%

TCR‐induced alteration of primary MHC peptide anchor residue

et al. 2019

View full text Add to dashboard Cite

The HLA‐A*02:01‐restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T‐cells‐1 (MART‐1) protein, represents one of the best‐studied tumor associated T‐cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA‐A*02:01 and TCRs from clinically relevant T‐cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5‐HLA‐A*02:01‐AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well‐studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

show abstract

Section: Discussionmentioning

confidence: 85%

TCR‐induced alteration of primary MHC peptide anchor residue

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The dynamic nature of peptides, especially those that are longer than 9 aa, in the HLA-binding groove is well established (57,58), as conformational plasticity plays an important role in enabling shape complementarity between TCR, peptide, and HLA. It is perhaps unsurprising that for highly dynamic peptides, multiple TCRs can recognize and bind the peptide in distinct conformations (19). However, 9-mer peptides, such as the NY-ESO-1 157-165 peptide, are usually more constrained, with different conformations typically being observed only as small backbone and side-chain rotamer movements (57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that off-target peptides do not need to share sequence, physiochemical, or backbone geometry with the cognate peptide (61,62), and, in addition, multiple TCRs can bind distinct peptide hotspots on the same pHLA (17). In one instance, this was driven by conformational plasticity in the peptide (19). In this study, we build on these observations to demonstrate that TCRs that recognize distinct peptide hotspots in the same peptide can display nonoverlapping specificity profiles, thereby providing a mechanism by which TCRs could potentially evade thymic deletion caused by a specific self-peptide.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide–HLA Complex

Coles

Mulvaney

Malla

et al. 2020

The Journal of Immunology

View full text Add to dashboard Cite

The molecular rules driving TCR cross-reactivity are poorly understood and, consequently, it is unclear the extent to which TCRs targeting the same Ag recognize the same off-target peptides. We determined TCR-peptide-HLA crystal structures and, using a single-chain peptide-HLA phage library, we generated peptide specificity profiles for three newly identified human TCRs specific for the cancer testis Ag NY-ESO-1 157-165-HLA-A2. Two TCRs engaged the same central peptide feature, although were more permissive at peripheral peptide positions and, accordingly, possessed partially overlapping peptide specificity profiles. The third TCR engaged a flipped peptide conformation, leading to the recognition of off-target peptides sharing little similarity with the cognate peptide. These data show that TCRs specific for a cognate peptide recognize discrete peptide repertoires and reconciles how an individual's limited TCR repertoire following negative selection in the thymus is able to recognize a vastly larger antigenic pool.

show abstract

“…Our data also demonstrate that Tcell recognition was significantly alleviated when we broke the MHC I salt bridge with R66A and E163A mutations. Previously determined complex structure between HLA-B*07:02 and KFJ37 TCR showed that both the R62 and E163 of HLA-B*07:02 can form hydrogen bonds with the residues in the CDR3α and CDR1α loops of the TCR, respectively (Chan et al, 2018). This indicated that the residues in the salt bridge can be directly-recognized by the TCR (Tynan et al, 2007).…”

Section: Figurementioning

confidence: 97%

Salt bridge-forming residues positioned over viral peptides presented by MHC class I impacts T-cell recognition in a binding-dependent manner

Niu

Peng

et al. 2019

Molecular Immunology

View full text Add to dashboard Cite

A B S T R A C TThe viral peptides presentation by major histocompatibility complex class I (MHC I) molecules play a pivotal role in T-cell recognition and the subsequent virus clearance. This process is delicately adjusted by the variant residues of MHC I, especially the residues in the peptide binding groove (PBG). In a series of MHC I molecules, a salt bridge is formed above the N-terminus of the peptides. However, the potential impact of the salt bridge on peptide binding and T-cell receptor (TCR) recognition of MHC I, as well as the corresponding molecular basis, are still largely unknown. Herein, we determined the structures of HLA-B*4001 and H-2K d in which two different types of salt bridges (Arg62-Glu163 or Arg66-Glu163) across the PBG were observed. Although the two salt bridges led to different conformation shifts of both the MHC I α helix and the peptides, binding of the peptides with the salt bridge residues was relatively conserved. Furthermore, through a series of in vitro and in vivo investigations, we found that MHC I mutations that disrupt the salt bridge alleviate peptide binding and can weaken the TCR recognition of MHC I-peptide complexes. Our study may provide key references for understanding MHC I-restricted peptide recognition by T-cells.

show abstract

Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide

Cited by 46 publications

References 63 publications

TCR‐induced alteration of primary MHC peptide anchor residue

TCR‐induced alteration of primary MHC peptide anchor residue

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide–HLA Complex

Salt bridge-forming residues positioned over viral peptides presented by MHC class I impacts T-cell recognition in a binding-dependent manner

Contact Info

Product

Resources

About