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Blood, 1 January 2007, Vol. 109, No. 1, pp. 235-243.
Prepublished online as a Blood First Edition Paper on September 12, 2006; DOI 10.1182/blood-2006-03-013318.
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IMMUNOBIOLOGY
Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex
Mirjam H. M. Heemskerk1,,
Renate S. Hagedoorn1,
Menno A. W. G. van der Hoorn1,
Lars T. van der Veken1,
Manja Hoogeboom1,
Michel G. D. Kester1,
Roel Willemze1, and
J. H. Frederik Falkenburg1
1 Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
Genetic engineering of T lymphocytes is an attractive strategy to specifically redirect T-cell immunity toward viral infections and malignancies. We previously demonstrated redirected antileukemic reactivity of cytomegalovirus (CMV)specific T cells by transfer of minor histocompatibility antigen HA-2specific T-cell receptors (TCRs). HA-2TCR-transferred CMV-specific T cells were potent effectors against HA-2expressing leukemic cells, as well as CMV-expressing cells. Functional activity of these T cells correlated with TCR cell-surface expression. In the present study we analyzed which properties of transferred and endogenous TCRs are crucial for efficient cell-surface expression. We demonstrate that expression of the introduced TCR is not a random process but is determined by characteristics of both the introduced and the endogenously expressed TCR. The efficiency of TCR cell-surface expression is controlled by the intrinsic quality of the TCR complex. In addition, we demonstrate that chimeric TCRs can be formed and that efficiency of TCR expression is independent of whether TCRs are retrovirally introduced or naturally expressed. In conclusion, introduced, endogenous, and chimeric TCRs compete for cell-surface expression in favor of the TCR-CD3 complex with best-pairing properties.

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