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Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode

Cole, David, Sami, Malkit, Scott, David, Rizkallah, Pierre, Borbulevych, Oleg Y., Todorov, Penio T., Moysey, Ruth K., Jakobsen, Bent K., Boulter, Jonathan M., Baker, Brian M. and Li, Yi 2013. Increased peptide contacts govern high affinity binding of a modified TCR whilst maintaining a native pMHC docking mode. Frontiers in Immunology 4 , 168. 10.3389/fimmu.2013.00168

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NaturalT cell receptors (TCRs) generally bind to their cognate pMHC molecules with weak affinity and fast kinetics, limiting their use as therapeutic agents. Using phage display, we have engineered a high affinity version of the A6 wild-type TCR (A6wt), specific for the human leukocyte antigen (HLA-A�0201) complexed with human T cell lymphotropic virus type 111–19 peptide (A2-Tax). Mutations in just 4 residues in the CDR3b loop region of the A6wt TCR were selected that improved binding to A2-Tax by nearly 1000-fold. Biophysical measurements of this mutant TCR (A6c134) demonstrated that the enhanced binding was derived through favorable enthalpy and a slower off-rate. The structure of the free A6c134 TCR and the A6c134/A2-Tax complex revealed a native binding mode, similar to the A6wt/A2-Tax complex. However, concordant with the more favorable binding enthalpy, the A6c134TCR made increased contacts with theTax peptide compared with the A6wt/A2- Tax complex, demonstrating a peptide-focused mechanism for the enhanced affinity that directly involved the mutated residues in the A6c134TCR CDR3b loop.This peptide-focused enhancedTCR binding may represent an important approach for developing antigen specific high affinity TCR reagents for use in T cell based therapies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Frontiers Research Foundation
ISSN: 1664-3224
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 12 June 2013
Last Modified: 04 Jun 2017 08:12

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