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¹ Program in Immunology and ² Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
³ Department of Immunology and ⁴ Department of Immunology/Biochemistry, University of Washington School of Medicine, Seattle, WA 98195
⁵ Department of Hematology and VanCreveld Clinic, Department of Immunology, University Medical Center Utrecht, 3584EA Utrecht, Netherlands
⁶ Department of Hematology and Oncology, University of Mainz, 51101 Mainz, Germany

CORRESPONDENCE Jürgen Kuball: j.h.e.kuball{at}umcutrecht.nl OR Philip D. Greenberg: pgreen{at}u.washington.edu

Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512–519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR or β chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (TCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or TCR chains bound tetramer equivalently at 4°C, but tetramer binding was enhanced at 37°C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.

Abbreviations used: TCR, TCR chains with reduced N-glycosylation; HLA-A2, HLA-A*0201; MFI, mean fluorescence intensity; N-X-S/T, asparagine–any amino acid–serine/threonine; NOD, nonobese diabetic; pMHC, peptide–MHC; SCID, severe combined immunodeficiency.

© 2009 Kuball et al.
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