Abstract
Reprogramming T-cell populations by T-cell receptor (TCR) gene transfer is a new therapeutic tool for adoptive tumor immunotherapy. Gene transfer of human leukocyte antigen (HLA)-transgenic mice-derived TCR into human T-cells allows the circumvention of tolerance to tumor-associated (self) antigens (TAA). This chapter reports on the identification of the α and β chains of the heterodimeric TCR derived from a mouse T-cell clone. The related DNA fragments are inserted into a retroviral vector for heterologous expression of the TAA-specific TCR in human T-cells. Polymerase chain reaction (PCR)-based cloning protocols are provided for the tailor-made customization of murine TCR. We describe the humanization and chimerization of such TCR as well as their expression in human T-cells.
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References
Yu, Z. and Restifo, N. P. (2002) Cancer vaccines: progress reveals new complexities. J. Clin. Invest. 110(3), 289–294.
Kessels, H. W., Wolkers, M. C., and Schumacher, T. N. (2002) Adoptive transfer of T-cell immunity. Trends Immunol. 23(5), 264–269.
Bankovich, A. J. and Garcia, K. C. (2003) Not just any T cell receptor will do. Immunity 18(1), 7–11.
Kane, L. P., Lin, J., and Weiss, A. (2000) Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12(3), 242–249.
Theobald, M., Biggs, J., Hernandez, J., Lustgarten, J., Labadie, C., Sherman, L. A. (1997) Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes. J. Exp. Med. 185(5), 833–841.
Kuball, J., Schuler, M., Antunes, FE., et al. (2002) Generating p53-specific cytotoxic T lymphocytes by recombinant adenoviral vector-based vaccination in mice, but not man. Gene Ther. 9(13), 833–843.
Stanislawski, T., Voss, R. H., Lotz, C., et al. (2001) Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat. Immunol. 2(10), 962–970.
Kessels, H. W., Wolkers, M. C., van den Boom, M. D., van der Valk, M. A., and Schumacher, T. N. (2001) Immunotherapy through TCR gene transfer. Nat. Immunol. 2(10), 957–961.
Holler, P. D. and Kranz, D. M. (2003) Quantitative analysis of the contribution of TCR/ pepMHC affinity and CD8 to T cell activation. Immunity 18(2), 255–264.
Lanzavecchia, A., Lezzi, G., and Viola, A. (1999) From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96(1), 1–4.
Rosenberg, S. A. (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10(3), 281–287.
Holler, P. D., Holman, P. O., Shusta, E. V., O’Herrin, S., Wittrup, K. D., and Kranz, D. M. (2000) In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proc. Natl. Acad. Sci. USA 97(10), 5387–5392.
Kessels, H. W., van den Boom, M. D., Spits, H., Hooijberg, E., and Schumacher, T. N. (2000) Changing T cell specificity by retroviral T cell receptor display. Proc. Natl. Acad. Sci. USA 97(26), 14,578–14,583.
Stauss, H. J. (1999) Immunotherapy with CTLs restricted by nonself MHC. Immunol. Today 20(4), 180–183.
Theobald, M., Biggs, J., Dittmer, D., Levine, A. J., and Sherman, L. A. (1995) Targeting p53 as a general tumor antigen. Proc. Natl. Acad. Sci. USA 92(26), 11,993–11,997.
Sherman, L. A., Hesse, S. V., Irwin, M. J., La Face, D., and Peterson, P. (1992) Selecting T cell receptors with high affinity for self-MHC by decreasing the contribution of CD8. Science 258(5083), 815–818.
Katayama, C. D., Eidelman, F. J., Duncan, A., Hooshmand, F., and Hedrick, S. M. (1995) Predicted complementarity determining regions of the T cell antigen receptor determine antigen specificity. EM BO J. 14(5), 927–938.
Breedveld, F. C. (2000) Therapeutic monoclonal antibodies. Lancet 355(9205), 735–740.
Eshhar, Z. (1997) Tumor-specific T-bodies: towards clinical application. Cancer Immunol. Immunother. 45(3-4), 131–136.
Labrecque, N., Whitfield, L. S., Obst, R., Waltzinger, C., Benoist, C., and Mathis, D. (2001) How much TCR does a T cell need? Immunity 15(1), 71–82.
Carson, G. R., Kuestner, R. E., Ahmed, A., Pettey, C. L., and Concino, M. F. (1991) Six chains of the human T cell antigen receptor.CD3 complex are necessary and sufficient for processing the receptor heterodimer to the cell surface. J Biol Chem. 266(12), 7883–7887.
Gouaillard, C., Huchenq-Champagne, A., Arnaud, J., Chen, C. L., and Rubin, B. (2001) Evolution of T cell receptor (TCR) alpha beta heterodimer assembly with the CD3 complex. EurJ. Immunol. 31(12), 3798–3805.
Li, Z. G., Wu, W. P., and Manolios, N. (1996) Structural mutations in the constant region of the T-cell antigen receptor (TCR)beta chain and their effect on TCR alpha and beta chain interaction. Immunology 88(4), 524–530.
Saito, T., Sussman, J. L., Ashwell, J. D., and Germain, R. N. (1989) Marked differences in the efficiency of expression of distinct alpha beta T cell receptor heterodimers. J. Immunol. 143(10), 3379–3384.
Uematsu, Y. (1992) Preferential association of alpha and beta chains of the T cell antigen receptor. Eur J. Immunol. 22(2), 603–606.
Burns, R. P., Jr., Natarajan, K., LoCascio, N. J., et al. (1998) Molecular analysis of skewed Tcra-V gene use in T-cell receptor beta-chain transgenic mice. Immunogenetics 47(2), 107–114.
Vacchio, M. S., Granger, L., Kanagawa, O., et al. (1993) T cell receptor V alpha-V beta combinatorial selection in the expressed T cell repertoire. J. Immunol. 151(3), 1322–1327.
Casrouge, A., Beaudoing, E., Dalle, S., Pannetier, C., Kanellopoulos, J., and Kourilsky, P. (2000) Size estimate of the alpha beta TCR repertoire of naive mouse splenocytes. J. Immunol. 164(11), 5782–5787.
Whitlow, M., Bell, B. A., Feng, S. L., et al. (1993) An improved linker for single-chain Fv with reduced aggregation and enhanced proteolytic stability. Protein Eng. 6(8), 989–995.
Robinson, C. R. and Sauer, R. T. (1998) Optimizing the stability of single-chain proteins by linker length and composition mutagenesis. Proc. Natl. Acad. Sci. USA 95(11), 5929–5934.
Chung, S., Wucherpfennig, K. W., Friedman, S. M., Hafler, D. A., and Strominger, J. L. (1994) Functional three-domain single-chain T-cell receptors. Proc. Natl. Acad. Sci. USA 91(26), 12,654–12,658.
Willemsen, R. A., Weijtens, M. E., Ronteltap, C., et al. (2000) Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR. Gene Ther. 7(16), 1369–1377.
Fitzer-Attas, C. J., Schindler, D. G., Waks, T., and Eshhar, Z. (1998) Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation. J. Immunol. 160(1), 145–154.
Johansson, B., Palmer, E., and Bolliger, L. (1999) The extracellular domain of the zetachain is essential for TCR function. J. Immunol. 162(2), 878–885.
Bolliger, L. and Johansson, B. (1999) Identification and functional characterization of the zeta-chain dimerization motif for TCR surface expression. J. Immunol. 163(7), 3867–3876.
Atwell, S., Ridgway, J. B., Wells, J. A., and Carter, P. (1997) Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J. Mol. Biol. 270(1), 26–35.
Garcia, K. C., Degano, M., Pease, L. R., et al. (1998) Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279(5354), 1166–1172.
Backstrom, B. T., Milia, E., Peter, A., Jaureguiberry, B., Baldari, C. T., and Palmer, E. (1996) A motif within the T cell receptor alpha chain constant region connecting peptide domain controls antigen responsiveness. Immunity 5(5), 437–447.
Rudd, P. M., Elliott, T., Cresswell, P., Wilson, I. A., and Dwek, R. A. (2001) Glycosylation and the immune system. Science 291(5512), 2370–2376.
Germain, R. N. (2002) T-cell development and the CD4-CD8 lineage decision. Nat. Rev. Immunol. 2(5), 309–322.
Naeher, D., Luescher, I. F., and Palmer, E. (2002) A role for the alpha-chain connecting peptide motif in mediating TCR-CD8 cooperation. J. Immunol. 169(6), 2964–2970.
Sette, A., Vitiello, A., Reherman, B., et al. (1994) The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J. Immunol. 153(12), 5586–5592.
Irwin, M. J., Heath, W. R., and Sherman, L. A. (1989) Species-restricted interactions between CD8 and the alpha 3 domain of class I influence the magnitude of the xenogeneic response. J. Exp. Med. 170(4), 1091–1101.
Gascoigne, N. R., Chien, Y., Becker, D. M., Kavaler, J., and Davis, M. M. (1984) Genomic organization and sequence of T-cell receptor beta-chain constant-and joining-region genes. Nature 310(5976), 387–391.
Lefranc, M. P., Giudicelli, V., Ginestoux, C., et al. (1999) IMGT, the international Immuno Gene Tics database. Nucleic Acids Res. 27(1), 209–212.
Ruiz, M., Giudicelli, V., Ginestoux, C., et al. (2000) IMGT, the international Immuno GeneTics database. Nucleic Acids Res. 28(1), 219–221.
Lefranc, M. P. (2001) IMGT, the international ImmunoGeneTics database. Nucleic Acids Res. 29(1), 207–209.
Lefranc, M. P. (2003) IMGT, the international ImmunoGeneTics database. Nucleic Acids Res. 31(1), 307–310.
Niederberger, N., Holmberg, K., Alam, S. M., et al. (2003) Allelic exclusion of the TCR alpha-chain is an active process requiring TCR-mediated signaling and c-Cbl. J. Immunol. 170(9), 4557–4563.
Sambrook, J., Fritsch, E. F., and Maniatis, T. (1989) Molecular Cloning. A Laboratory Manual, 2nd Ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
Weijtens, M. E., Hart, E. H., and Bolhuis, R. L. (2000) Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production. Gene Ther. 7(1), 35–42.
Weijtens, M. E., Willemsen, R. A., Hart, E. H., and Bolhuis, R. L. (1998) A retroviral vector system “STITCH” in combination with an optimized single chain antibody chimeric receptor gene structure allows efficient gene transduction and expression in human T lymphocytes. Gene Ther. 5(9), 1195–1203.
Tuan, R. S. (1997) Recombinant Gene Expression Protocols. 1st Ed. Human Press Inc., Totowa, NJ.
Call, M. E., Pyrdol, J., Wiedmann, M., and Wucherpfennig, K. W. (2002) The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 111(7), 967–979.
Rudd, P. M., Wormald, M. R., Stanfield, R. L., et al. (1999) Roles for glycosylation of cell surface receptors involved in cellular immune recognition. J. Mol. Biol. 293(2), 351–366.
Arden, B., Clark, S. P., Kabelitz, D., and Mak, T. W. (1995) Mouse T-cell receptor variable gene segment families. Immunogenetics 42(6), 501–530.
Gurtu, V., Yan, G., and Zhang, G. (1996) IRES bicistronic expression vectors for efficient creation of stable mammalian cell lines. Biochem. Biophys. Res. Commun. 229(1), 295–298.
Mizuguchi, H., Xu, Z., Ishii-Watabe, A., Uchida, E., and Hayakawa, T. (2000) IRES dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol. Ther. 1(4), 376–382.
Jackson, M. R., Nilsson, T., and Peterson, P. A. (1990) Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum. EMBO J. 9(10), 3153–3162.
Bunnell, B. A., Muul, L. M., Donahue, R. E., Blaese, R. M., and Morgan, R. A. (1995) High-efficiency retroviral-mediated gene transfer into human and nonhuman primate pe-ripheral blood lymphocytes. Proc. Natl. Acad. Sci. USA 92(17), 7739–7743.
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Voss, RH., Kuball, J., Theobald, M. (2005). Designing TCR for Cancer Immunotherapy. In: Ludewig, B., Hoffmann, M.W. (eds) Adoptive Immunotherapy: Methods and Protocols. Methods in Molecular Medicine™, vol 109. Humana Press. https://doi.org/10.1385/1-59259-862-5:229
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DOI: https://doi.org/10.1385/1-59259-862-5:229
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