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TCRs with distinct specificity profiles use different binding modes to engage an identical peptide–HLA complex

DOI: 10.4049/jimmunol.1900915 DOI Help

Authors: Charlotte Coles (Immunocore, Ltd) , Rachel M. Mulvaney (Immunocore, Ltd) , Sunir Malla (Immunocore, Ltd) , Andrew Walker (Immunocore, Ltd) , Kathrine J. Smith (GlaxoSmithKline) , Angharad Lloyd (Cardiff University) , Kate L. Lowe (Immunocore, Ltd) , Michelle L. Mccully (Immunocore, Ltd) , Ruth Martinez Hague (Immunocore, Ltd) , Milos Aleksic (Immunocore, Ltd) , Jane Harper (Immunocore, Ltd) , Samantha J. Paston (Immunocore, Ltd) , Zoe Donnellan (Immunocore, Ltd) , Fiona Chester (Immunocore, Ltd) , Katrin Wiederhold (Immunocore, Ltd) , Ross A. Robinson (Immunocore, Ltd) , Andrew Knox (Immunocore, Ltd) , Andrew R. Stacey (Immunocore, Ltd) , Joseph Dukes (Immunocore, Ltd) , Emma Baston (Immunocore, Ltd) , Sue Griffin (GlaxoSmithKline) , Bent K. Jakobsen (Immunocore, Ltd) , Annelise Vuidepot (Immunocore, Ltd) , Stephen Harper (Immunocore, Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Immunology , VOL 204 , PAGES 1943-1953

State: Published (Approved)
Published: April 2020

Open Access Open Access

Abstract: 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-1157–165–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.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)


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