High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines

Yangbing Zhao, Alan D. Bennett, Zhili Zheng, Qiong J. Wang, Paul F. Robbins, Lawrence Y.L. Yu, Yi Li, Peter E. Molloy, Steven M. Dunn, Bent K. Jakobsen, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

Abstract

We examined the activity of human T cells engineered to express variants of a single TCR (1G4) specific for the cancer/testis Ag NY-ESO-1, generated by bacteriophage display with a wide range of affinities (from 4 μM to 26 pM). CD8+ T cells expressing intermediate- and high-affinity 1G4 TCR variants bound NY-ESO-1/HLA-A2 tetramers with high avidity and Ag specificity, but increased affinity was associated with a loss of target cell specificity of the TCR gene-modified cells. T cells expressing the highest affinity TCR (K D value of 26 pM) completely lost Ag specificity. The TCRs with affinities in the midrange, KD 5 and 85 nM, showed specificity only when CD8 was absent or blocked, while the variant TCRs with affinities in the intermediate range - with KD values of 450 nM and 4 μM-demonstrated Ag-specific recognition. Although the biological activity of these two relatively low-affinity TCRs was comparable to wild-type reactivity in CD8+ T cells, introduction of these TCR dramatically increased the reactivity of CD4+ T cells to tumor cell lines.

Original languageEnglish (US)
Pages (from-to)5845-5854
Number of pages10
JournalJournal of Immunology
Volume179
Issue number9
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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