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Plasticity in the contribution of T cell receptor variable region residues to binding of peptide-HLA-A2 complexes

Item Type:Article
Title:Plasticity in the contribution of T cell receptor variable region residues to binding of peptide-HLA-A2 complexes
Creators Name:Smith, S.N. and Sommermeyer, D. and Piepenbrink, K.H. and Blevins, S.J. and Bernhard, H. and Uckert, W. and Baker, B.M. and Kranz, D.M.
Abstract:One hypothesis accounting for major histocompatibility complex (MHC) restriction by T cell receptors (TCRs) holds that there are several evolutionary conserved residues in TCR variable regions that contact MHC. While this "germline codon" hypothesis is supported by various lines of evidence, it has been difficult to test. The difficulty stems in part from the fact that TCRs exhibit low affinities for pep/MHC, thus limiting the range of binding energies that can be assigned to these key interactions using mutational analyses. To measure the magnitude of binding energies involved, here we used high-affinity TCRs engineered by mutagenesis of CDR3. The TCRs included a high-affinity, MART-1/HLA-A2-specific single-chain TCR and two other high-affinity TCRs that all contain the same Valpha region and recognize the same MHC allele (HLA-A2), with different peptides and Vbeta regions. Mutational analysis of residues in CDR1 and CDR2 of the three Valpha2 regions showed the importance of the key germline codon residue Y51. However, two other proposed key residues showed significant differences among the TCRs in their relative contributions to binding. With the use of single-position, yeast-display libraries in two of the key residues, MART-1/HLA-A2 selections also revealed strong preferences for wild-type germline codon residues, but several alternative residues could also accommodate binding and, hence, MHC restriction. Thus, although a single residue (Y51) could account for a proportion of the energy associated with positive selection (i.e., MHC restriction), there is significant plasticity in requirements for particular side chains in CDR1 and CDR2 and in their relative binding contributions among different TCRs.
Keywords:T Cell Receptors, Single-Chain, Yeast Display, Directed Evolution, Germline Codon Bias
Source:Journal of Molecular Biology
ISSN:0022-2836
Publisher:Elsevier (The Netherlands)
Volume:425
Number:22
Page Range:4496-4507
Date:15 November 2013
Official Publication:https://doi.org/10.1016/j.jmb.2013.08.007
PubMed:View item in PubMed

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