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TCR-engineered T cells: a model of inducible TCR expression to dissect the interrelationship between two TCRs

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Item Type:Article
Title:TCR-engineered T cells: a model of inducible TCR expression to dissect the interrelationship between two TCRs
Creators Name:Reuß, S. and Sebestyén, Z. and Heinz, N. and Loew, R. and Baum, C. and Debets, R. and Uckert, W.
Abstract:TCR gene-modified T cells for adoptive therapy simultaneously express the transgenic (tg) TCR and the endogenous TCR which might lead to mispaired TCRs with harmful unknown specificity and to a reduced function of TCR-tg T cells. We generated dual TCR T cells in two settings in which either TCR was constitutively expressed by a retroviral promoter while the second TCR expression was regulable by a tet-on system. Constitutively expressed TCR molecules were reduced on the cell surface depending on the induced TCR expression leading to strongly hampered function. Besides that, using fluorescence resonance energy transfer (FRET) we detected mispaired TCR dimers and different pairing behaviors of individual TCR chains with a mutual influence on TCR chain expression. The loss of function and mispairing could not be avoided by changing the TCR expression level or by introduction of an additional cysteine bridge. However, in polyclonal T cells, optimized TCR formats (cysteineization, codon optimization) enhanced correct pairing and function. We conclude from our data that (i) the level of mispairing depends on the individual TCRs and is not reduced by increasing the level of one TCR, and (ii) modifications (cysteineization, codon optimization) improve correct pairing but do not completely exclude mispairing (cysteineization).
Keywords:TCR Gene Therapy, TCR Mispairing, TCR Gene Optimization, Inducible Gene Expression, Fluorescence Resonance Energy Transfer (FRET)
Source:European Journal of Immunology
Publisher:Wiley (U.S.A.)
Page Range:265-274
Date:January 2014
Official Publication:https://doi.org/10.1002/eji.201343591
PubMed:View item in PubMed

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