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Transgenic mice with a diverse human T cell antigen receptor repertoire


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.


  1. 1

    Hedrick, S.M., Cohen, D.I., Nielsen, E.A. & Davis, M.M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–153 (1984).

    CAS  Article  Google Scholar 

  2. 2

    Yanagi, Y. et al. A human T cell–specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984).

    CAS  Article  Google Scholar 

  3. 3

    Chien, Y.H., Gascoigne, N.R.J., Kavaler, J., Lee, N.E. & Davis, M.M. Somatic recombination in a murine T cell receptor gene. Nature 309, 322–326 (1984).

    CAS  Article  Google Scholar 

  4. 4

    Kisielow, P., Teh, H.S., Bluthmann, H. & von Boehmer, H. Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 335, 730–733 (1988).

    CAS  Article  Google Scholar 

  5. 5

    Sha, W.C. et al. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 336, 73–76 (1988).

    CAS  Article  Google Scholar 

  6. 6

    Jameson, S.C., Hogquist, K.A. & Bevan, M.J. Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Tanchot, C., Lemonnier, F.A., Pérarnau, B., Freitas, A.A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Zinkernagel, R.M. & Doherty, P.C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–702 (1974).

    CAS  Article  Google Scholar 

  9. 9

    Zinkernagel, R.M. et al. On the thymus in the differentiation of “H-2 self-recognition” by T cells: evidence for dual recognition? J. Exp. Med. 147, 882–896 (1978).

    CAS  Article  Google Scholar 

  10. 10

    Blackman, M. et al. The T cell repertoire may be biased in favor of MHC recognition. Cell 47, 349–357 (1986).

    CAS  Article  Google Scholar 

  11. 11

    Zerrahn, J., Held, W. & Raulet, D.H. The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L. & Kappler, J.W. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 26, 171–203 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Scott-Browne, J.P., White, J., Kappler, J.W., Gapin, L. & Marrack, P. Germline-encoded amino acids in the αβ T cell receptor control thymic selection. Nature 458, 1043–1046 (2009).

    CAS  Article  Google Scholar 

  14. 14

    Kreslavsky, T., Gleimer, M. & von Boehmer, H. αβ versus γδ lineage choice at the first TCR-controlled checkpoint. Curr. Opin. Immunol. 22, 185–192 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Sensi, M. et al. Cytotoxic T lymphocyte clones from different patients display limited T-cell-receptor variable-region gene usage in HLA-A2–restricted recognition of the melanoma antigen Melan-A/MART-1. Proc. Natl. Acad. Sci. USA 92, 5674–5678 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Dietrich, P.-Y. et al. Melanoma patients respond to a cytotoxic T lymphocyte–defined self-peptide with diverse and nonoverlapping T-cell receptor repertoires. Cancer Res. 61, 2047–2054 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Mantovani, S. et al. Dominant TCR-α requirements for a self antigen recognition in humans. J. Immunol. 169, 6253–6260 (2002).

    CAS  Article  Google Scholar 

  18. 18

    Trautmann, L. et al. Dominant TCR Vα usage by virus and tumor-reactive T cells with wide affinity ranges for their specific antigens. Eur. J. Immunol. 32, 3181–3190 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Mantovani, S. et al. Molecular and functional bases of self-antigen recognition in long-term persistent melanocyte-specific CD8+ T cells in one vitiligo patient. J. Invest. Dermatol. 121, 308–314 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Sherman, L.A. et al. Strategies for tumor elimination by cytotoxic T lymphocytes. Crit. Rev. Immunol. 18, 47–54 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Schumacher, T.N. T-cell-receptor gene therapy. Nat. Rev. Immunol. 2, 512–519 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Pascolo, S. et al. HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β2 microglobulin (β2m) HLA-A2.1 monochain transgenic H-2Db β2m double knockout mice. J. Exp. Med. 185, 2043–2051 (1997).

    CAS  Article  Google Scholar 

  23. 23

    Mombaerts, P. et al. Mutations in T cell antigen receptor genes α and β block thymocyte development at different stages. Nature 360, 225–231 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Dudley, E.C., Girardi, M., Owen, M.J. & Hayday, A.C. αβ and γ∂ T cells can share a late common precursor. Curr. Biol. 5, 659–669 (1995).

    CAS  Article  Google Scholar 

  25. 25

    Kang, J., Volkmann, A. & Raulet, D.H. Evidence that γδ versus αβ T cell fate determination is initiated independently of T cell signaling. J. Exp. Med. 193, 689–698 (2001).

    CAS  Article  Google Scholar 

  26. 26

    Joachims, M.L., Chain, J.L., Hooker, S.W., Knott-Craig, C.J. & Thompson, L.F. Human αβ and γδ thymocyte development: TCR gene rearrangements, intracellular TCRβ expression and γδ developmental potential—differences between men and mice. J. Immunol. 176, 1543–1552 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Kreslavsky, T., Garbe, A.I., Krueger, A. & von Boehmer, H. T cell receptor–instructed αβ versus γδ lineage commitment revealed by single-cell analysis. J. Exp. Med. 205, 1173–1186 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Burtrum, D.B., Kim, S., Dudley, E.C., Hayday, A.C. & Petrie, H.T. TCR gene recombination and αβ-γδ lineage divergence: productive TCR-β rearrangement is neither exclusive nor preclusive of γδ cell development. J. Immunol. 157, 4293–4296 (1996).

    CAS  PubMed  Google Scholar 

  29. 29

    Almeida, A.R.M., Borghans, J.A.M. & Freitas, A.A. T cell homeostasis: Thymus regeneration and peripheral T cell restoration in mice with a reduced fraction of competent precursors. J. Exp. Med. 194, 591–599 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Lonberg, N. et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859 (1994).

    CAS  Article  Google Scholar 

  31. 31

    Arstila, T.P. et al. A direct estimate of the human αβ T cell receptor diversity. Science 286, 958–961 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Casrouge, A. et al. Size estimate of the αβ TCR repertoire of naïve mouse splenocytes. J. Immunol. 164, 5782–5787 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Alexander, J. et al. Derivation of HLA-A11/Kb transgenic mice: functional CTL repertoire and recognition of human A11-restricted CTL epitopes. J. Immunol. 159, 4753–4761 (1997).

    CAS  PubMed  Google Scholar 

  34. 34

    Markie, D. (ed.) YAC Protocols. Meth. Mol. Biol. 54 (Humana, 1995).

  35. 35

    Engels, B. et al. Retroviral vectors for high-level transgene expression in T lymphocytes. Hum. Gene Ther. 14, 1155–1168 (2003).

    CAS  Article  Google Scholar 

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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.

Corresponding author

Correspondence to Thomas Blankenstein.

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The authors declare no competing financial interests.

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

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Li, LP., Lampert, J., Chen, X. et al. Transgenic mice with a diverse human T cell antigen receptor repertoire. Nat Med 16, 1029–1034 (2010).

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