Changing the peptide specificity of a human T-cell receptor by directed evolution

Sheena N. Smith, Yuhang Wang, Javier L. Baylon, Nishant K. Singh, Brian M. Baker, Emad Tajkhorshid and David M. Kranz ()
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Sheena N. Smith: University of Illinois
Yuhang Wang: Center for Biophysics and Computational Biology, University of Illinois
Javier L. Baylon: Center for Biophysics and Computational Biology, University of Illinois
Nishant K. Singh: University of Notre Dame
Brian M. Baker: University of Notre Dame
Emad Tajkhorshid: University of Illinois
David M. Kranz: University of Illinois

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Binding of a T-cell receptor (TCR) to a peptide/major histocompatibility complex is the key interaction involved in antigen specificity of T cells. The recognition involves up to six complementarity determining regions (CDR) of the TCR. Efforts to examine the structural basis of these interactions and to exploit them in adoptive T-cell therapies has required the isolation of specific T-cell clones and their clonotypic TCRs. Here we describe a strategy using in vitro-directed evolution of a single TCR to change its peptide specificity, thereby avoiding the need to isolate T-cell clones. The human TCR A6, which recognizes the viral peptide Tax/HLA-A2, was converted to TCR variants that recognized the cancer peptide MART1/HLA-A2. Mutational studies and molecular dynamics simulations identified CDR residues that were predicted to be important in the specificity switch. Thus, in vitro engineering strategies alone can be used to discover TCRs with desired specificities.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6223

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DOI: 10.1038/ncomms6223

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