Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Induction of tolerance and immunity by redirected B cell-specific cytolytic T lymphocytes

Gene Therapy volume 14, pages 1739–1749 (2007)Cite this article

Abstract

Chimeric receptors bearing ligand recognition domains linked to signaling regions from the T-cell receptor can redirect T lymphocytes against non-MHC-restricted targets. Cytolytic T lymphocytes (CTL) expressing these chimeric receptors are being tested in preclinical and clinical trials for activity in cancer, infectious diseases and autoimmunity. The chimeric receptors may incorporate antigenic epitopes previously unrecognized by the immune system. Whether a receptor-specific antibody response develops to these neoantigens and whether such a response inhibits therapeutic cell activity is unknown. We hypothesized that upon engagement of a chimeric receptor-specific B cell, receptor-modified CTL will be activated, lysing the B cell and inducing tolerance to the chimeric receptor rather than immunity. We demonstrate that receptor-modified CTL are indeed stimulated by cognate receptor-specific B cells, proliferate and produce cytokines in response and kill the B cells in vitro and in vivo. However, this is insufficient to induce full B-cell tolerance. Modified CTL induce a chimeric receptor-specific antibody response independent of any other source of antigen. Nevertheless, the CTL retain substantial activity even in the presence of saturating doses of receptor-specific antibody. Thus antichimeric receptor antibody responses need to be considered in the clinical use of chimeric receptor-modified T cells. However, the inhibitory activity of these antibodies may in cases be limited.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Tey SK, Bollard CM, Heslop HE . Adoptive T-cell transfer in cancer immunotherapy. Immunol Cell Biol 2006; 84: 281–289.

    Article  CAS  PubMed  Google Scholar 

  2. Gattinoni L, Powell Jr DJ, Rosenberg SA, Restifo NP . Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 2006; 6: 383–393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Riddell SR, Greenberg PD . Principles for adoptive T cell therapy of human viral diseases. Annu Rev Immunol 1995; 13: 545–586.

    Article  CAS  PubMed  Google Scholar 

  4. Starr TK, Jameson SC, Hogquist KA . Positive and negative selection of T cells. Annu Rev Immunol 2003; 21: 139–176.

    Article  CAS  PubMed  Google Scholar 

  5. Janeway Jr CA . The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu Rev Immunol 1992; 10: 645–674.

    Article  CAS  PubMed  Google Scholar 

  6. Rossig C, Brenner MK . Chimeric T-cell receptors for the targeting of cancer cells. Acta Haematol 2003; 110: 154–159.

    Article  PubMed  Google Scholar 

  7. Geiger TL, Jyothi MD . Development and application of receptor-modified T lymphocytes for adoptive immunotherapy. Transfus Med Rev 2001; 15: 21–34.

    Article  CAS  PubMed  Google Scholar 

  8. Roberts MR, Qin L, Zhang D, Smith DH, Tran AC, Dull TJ et al. Targeting of human immunodeficiency virus-infected cells by CD8+ T lymphocytes armed with universal T-cell receptors. Blood 1994; 84: 2878–2889.

    CAS  PubMed  Google Scholar 

  9. Sadelain M, Riviere I, Brentjens R . Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer 2003; 3: 35–45.

    Article  CAS  PubMed  Google Scholar 

  10. Jyothi MD, Flavell RA, Geiger TL . Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes. Nat Biotechnol 2002; 20: 1215–1220.

    Article  CAS  PubMed  Google Scholar 

  11. Nguyen P, Geiger TL . Antigen-specific targeting of CD8(+) T cells with receptor-modified T lymphocytes. Gene Therapy 2003; 10: 594–604.

    Article  CAS  PubMed  Google Scholar 

  12. Mekala DJ, Geiger TL . Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Blood 2005; 105: 2090–2092.

    Article  CAS  PubMed  Google Scholar 

  13. Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood 2000; 96: 785–793.

    CAS  PubMed  Google Scholar 

  14. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 2006; 12 (20 Part 1): 6106–6115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Deeks SG, Wagner B, Anton PA, Mitsuyasu RT, Scadden DT, Huang C et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol Ther 2002; 5: 788–797.

    Article  CAS  PubMed  Google Scholar 

  16. Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood 2000; 96: 467–474.

    CAS  PubMed  Google Scholar 

  17. Stripecke R, Carmen VM, Skelton D, Satake N, Halene S, Kohn D . Immune response to green fluorescent protein: implications for gene therapy. Gene Therapy 1999; 6: 1305–1312.

    Article  CAS  PubMed  Google Scholar 

  18. Cahalan MD, Parker I . Close encounters of the first and second kind: T-DC and T-B interactions in the lymph node. Semin Immunol 2005; 17: 442–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 2006; 66: 10995–11004.

    Article  CAS  PubMed  Google Scholar 

  20. Moeller M, Haynes NM, Trapani JA, Teng MW, Jackson JT, Tanner JE et al. A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells. Cancer Gene Ther 2004; 11: 371–379.

    Article  CAS  PubMed  Google Scholar 

  21. Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M . Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 1998; 188: 619–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nguyen P, Moisini I, Geiger TL . Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function. Blood 2003; 102: 4320–4325.

    Article  CAS  PubMed  Google Scholar 

  23. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 1988; 334: 676–682.

    Article  CAS  PubMed  Google Scholar 

  24. Lanzavecchia A, Lezzi G, Viola A . From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 1999; 96: 1–4.

    Article  CAS  PubMed  Google Scholar 

  25. Geiger TL, Nguyen P, Leitenberg D, Flavell RA . Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes. Blood 2001; 98: 2364–2371.

    Article  CAS  PubMed  Google Scholar 

  26. Russell DM, Dembic Z, Morahan G, Miller JF, Burki K, Nemazee D . Peripheral deletion of self-reactive B cells. Nature 1991; 354: 308–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D, Simister NE . Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn. Immunology 1996; 89: 573–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fabre JW . The allogeneic response and tumor immunity. Nat Med 2001; 7: 649–652.

    Article  CAS  PubMed  Google Scholar 

  29. Bitton N, Gorochov G, Debre P, Eshhar Z . Gene therapy approaches to HIV-infection: immunological strategies: use of T bodies and universal receptors to redirect cytolytic T-cells. Front Biosci 1999; 4: D386–D393.

    Article  CAS  PubMed  Google Scholar 

  30. Westermann J, Ehlers EM, Exton MS, Kaiser M, Bode U . Migration of naive, effector and memory T cells: implications for the regulation of immune responses. Immunol Rev 2001; 184: 20–37.

    Article  CAS  PubMed  Google Scholar 

  31. Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med 1993; 178: 361–366.

    Article  CAS  PubMed  Google Scholar 

  32. Persons DA, Allay JA, Allay ER, Smeyne RJ, Ashmun RA, Sorrentino BP et al. Retroviral-mediated transfer of the green fluorescent protein gene into murine hematopoietic cells facilitates scoring and selection of transduced progenitors in vitro and identification of genetically modified cells in vivo. Blood 1997; 90: 1777–1786.

    CAS  PubMed  Google Scholar 

  33. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA et al. Current Protocols in Molecular Biology. John Wiley and Sons: New York, 1989.

    Google Scholar 

Download references

Acknowledgements

We thank Richard Cross and Jennifer Smith for assistance with flow cytometric sorting and cytokine analysis. This work was supported by the National Institutes of Health grant R01 AI056153 (to TLG) and by the American Lebanese Syrian Associated Charities/St Jude Children's Research Hospital (to PN, CTD and TLG). PN and CTD performed research and analyzed data, and TLG designed research and analyzed data.

Author information

Authors and Affiliations

  1. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    P Nguyen, C T Duthoit & T L Geiger

Authors
  1. P Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C T Duthoit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T L Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T L Geiger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nguyen, P., Duthoit, C. & Geiger, T. Induction of tolerance and immunity by redirected B cell-specific cytolytic T lymphocytes. Gene Ther 14, 1739–1749 (2007). https://doi.org/10.1038/sj.gt.3303045

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3303045

Keywords

Search

Advanced search

Quick links