Abstract
Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B∗07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B∗07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition.
| Original language | English |
|---|---|
| Article number | 1026 |
| Number of pages | 13 |
| Journal | Nature Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
Keywords
- adaptive immunity
- antigen processing and presentation
- tumour immunology
- x-ray crystallography
Cite this
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Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide. / Chan, Kok Fei; Gully, Benjamin S.; Gras, Stephanie; Beringer, Dennis X.; Kjer-Nielsen, Lars; Cebon, Jonathan; McCluskey, James; Chen, Weisan; Rossjohn, Jamie.
In: Nature Communications, Vol. 9, No. 1, 1026, 01.12.2018.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide
AU - Chan, Kok Fei
AU - Gully, Benjamin S.
AU - Gras, Stephanie
AU - Beringer, Dennis X.
AU - Kjer-Nielsen, Lars
AU - Cebon, Jonathan
AU - McCluskey, James
AU - Chen, Weisan
AU - Rossjohn, Jamie
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B∗07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B∗07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition.
AB - Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B∗07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B∗07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition.
KW - adaptive immunity
KW - antigen processing and presentation
KW - tumour immunology
KW - x-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85044217316&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03321-w
DO - 10.1038/s41467-018-03321-w
M3 - Article
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1026
ER -