High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines.
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 microM 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, K(D) 5 and 85 nM, showed specificity only when CD8 was absent or blocked, while the variant TCRs with affinities in the intermediate range-with K(D) values of 450 nM and 4 microM-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.
Zhao
Yangbing
Y
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Bennett
Alan D
AD
Zheng
Zhili
Z
Wang
Qiong J
QJ
Robbins
Paul F
PF
Yu
Lawrence Y L
LY
Li
Yi
Y
Molloy
Peter E
PE
Dunn
Steven M
SM
Jakobsen
Bent K
BK
Rosenberg
Steven A
SA
Morgan
Richard A
RA
D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D003429:Cross Reactions / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D012680:Sensitivity and Specificity
D006649:Histocompatibility Antigens; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell