Sheena N. Smith, Yuhang Wang, Javier L. Baylon, Nishant K. Singh, Brian M.
Baker, Emad Tajkhorshid, and David M. Kranz.
Changing the peptide specificity of a human T-cell receptor by
directed evolution.
Nature Communications, 5:5223, 2014.
(13 pages).
(PMC: PMC4225554)
SMIT2014-ET
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.
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