Submitted March 28, 2006
Accepted July 24, 2006
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. Heemskerk*, Renate S. Hagedoorn, Menno A.W.G. van der Hoorn, Lars T. van der Veken, Manja Hoogeboom, Michel G.D. Kester, Roel Willemze, and J. H. Frederik Falkenburg
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
* Corresponding author; email: mhmheemskerk{at}lumc.nl.
Genetic engineering of T lymphocytes is an attractive strategy to specifically redirect T cell immunity towards viral infections and malignancies. We previously demonstrated redirected anti-leukemic reactivity of CMV specific T cells by transfer of minor histocompatibility antigen HA-2 specific TCRs. HA-2-TCR-transferred CMV specific T cells were potent effectors against HA-2 expressing 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.
