Transgenic mice with a diverse human T cell antigen receptor repertoire

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Abstract

Because of tolerance mechanisms, it has been hard to identify the T cell receptors (TCRs) of high-avidity T cells against self (for example, tumor) antigens. TCRs that are specific for foreign human antigens from the nontolerant T cell repertoire can be identified in mice. Moreover, if mice are constructed to express the human TCR repertoire, they can be used to analyze the unskewed repertoire against human self antigens. Here we generated transgenic mice with the entire human TCRαβ gene loci (1.1 and 0.7 Mb), whose T cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency. A human major histocompatibility class I transgene increases the generation of CD8+ T cells with human compared to mouse TCRs. Functional CD8+ T cells against several human tumor antigens were induced, and those against the Melan-A melanoma antigen used similar TCRs to those that have been detected in T cell clones from individuals with autoimmune vitiligo or melanoma. These mice will allow researchers to identify pathogenic and therapeutic human TCRs.

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Figure 1: Generation of mice transgenic for the human TCRα and TCRβ gene loci.
Figure 2: T cell development in human TCRαβ gene loci transgenic mice with a diverse TCR repertoire.
Figure 3: CD8+ T cells in ABabDII mice are functional and use similar TCRs as human CD8+ T cells against an immunogenic antigen.
Figure 4: Specific CD8+ T cell responses against a panel of human TAAs in ABabDII mice.

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Acknowledgements

We thank M. Textor, M. Rösch, A. Gärtner and C. Westen for technical assistance; A. Garratt, E. Rohde and A. Samuels for help with ES cell culture; M. Hafner and M. Ebel for ES cell injection; H.-P. Rahn for FACS sorting; M. Gong for help with spectratyping and statistical analysis; F. Lemonier (Institut Pasteur) for HHDII mice; E. Mcintyre (Hôpital Necker) and E. Green (US National Institutes of Health) for YACs; and D. Schendel and D. Busch for critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich TR36) and the Helmholtz-Gemeinschaft Deutscher Forschungszentren (HA-202). W.M. was supported by the European Commission program MUGEN LSHG-CT-2005-005203 at the Helmholtz Centre for Infection Research, Braunschweig, Germany.

Author information

L.-P.L. designed experimental strategies and contributed to writing of the manuscript. He contributed Figures 1c, 2a–c and 3, Supplementary Figures 3, 5–7 and 9, Table 1 and Supplementary Tables 1–3. J.C.L. contributed to experimental design and to Figures 1d and 2c, Supplementary Figure 4 and Supplementary Tables 1 and 3. X.C. contributed to Figures 2d, 3d and 4, Supplementary Figure 10 and Supplementary Table 1. C.L. contributed to Figure 4 and Supplementary Figure 8. J.P. contributed to Figure 4. W.M. was responsible for microinjection of ES cells to obtain chimeric mice. T.B. proposed and supervised the project, interpreted data and wrote the manuscript.

Correspondence to Thomas Blankenstein.

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Supplementary Figures 1–10, Supplementary Tables 1–3 and Supplementary Methods (PDF 903 kb)

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