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, David M. Kranz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5223
JournalNature communications
Volume5
DOIs
StatePublished - Jan 1 2014

Fingerprint

T-Cell Antigen Receptor
T-cells
peptides
clone cells
Peptides
Complementarity Determining Regions
HLA-A2 Antigen
T-Lymphocytes
Clone Cells
T-Cell Antigen Receptor Specificity
antigens
Molecular Dynamics Simulation
Cell- and Tissue-Based Therapy
Major Histocompatibility Complex
Molecular dynamics
therapy
isolation
switches
cancer
Switches

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Changing the peptide specificity of a human T-cell receptor by directed evolution. / Smith, Sheena N.; Wang, Yuhang; Baylon, Javier L.; Singh, Nishant K.; Baker, Brian M.; Tajkhorshid, Emad; Kranz, David M.

In: Nature communications, Vol. 5, 5223, 01.01.2014.

Research output: Contribution to journalArticle

Smith, Sheena N. ; Wang, Yuhang ; Baylon, Javier L. ; Singh, Nishant K. ; Baker, Brian M. ; Tajkhorshid, Emad ; Kranz, David M. / Changing the peptide specificity of a human T-cell receptor by directed evolution. In: Nature communications. 2014 ; Vol. 5.
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