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β T Cell Receptor Transfer to T Cells Generates Functional Effector Cells without Mixed TCR Dimers In Vivo¹

Lars T. van der Veken^2,*, Miriam Coccoris^2,, Erwin Swart, J. H. Frederik Falkenburg^*, Ton N. Schumacher and Mirjam H. M. Heemskerk^3,*

^* Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; and Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

The successful application of T cell-based immunotherapeutic applications depends on the availability of large numbers of T cells with the desired Ag specificity and phenotypic characteristics. Engineering of TCR-transferred T lymphocytes is an attractive strategy to obtain sufficient T cells with an Ag specificity of choice. However, the introduction of additional TCR chains into T cells leads to the generation of T cells with unknown specificity, due to the formation of mixed dimers between the endogenous and introduced TCR chains. The formation of such potentially autoaggressive T cells may be prevented by using T cells as recipient cells, but the in vivo activity of such TCR-engineered T cells has not been established. In the present study, we have investigated the in vivo functionality of TCR-transduced T cells, in particular their Ag specific proliferative capacity, Ag specific reactivity, in vivo persistence, and their capacity to mount recall responses. The results demonstrate that β TCR engineering of T cells forms a feasible strategy to generate Ag-specific effector T cells that do not express mixed TCR dimers. In view of increasing concerns on the potential autoimmune consequences of mixed TCR dimer formation, the testing of β TCR engineered T cells in clinical trials seems warranted.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ L.V. was supported by grant 2001-2490 from the Dutch Cancer Society. M.C. was supported by the European Union 6th Framework program (ATTACK).

Lars T. van der Veken designed research, performed research, analyzed data, and wrote the paper; Miriam Coccoris designed research, performed research, analyzed data, and wrote the paper; Erwin Swart performed research; J. H. Frederik Falkenburg designed research and wrote the paper; Ton N. Schumacher designed research and wrote the paper; and Mirjam H. M. Heemskerk designed research, analyzed data, and wrote the paper.

² L.V. and M.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Mirjam H. M. Heemskerk, Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: MHMHeemskerk{at}LUMC.nl

⁴ Abbreviations used in this paper: IEL, intra epithelial lymphocyte; LP, lamina propria.