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.

  • Article
  • Published:

Dual receptor T cells extend the immune repertoire for foreign antigens

Nature Immunology volume 3, pages 127–134 (2002)Cite this article

Abstract

Since the discovery of T cells that express two T cell receptors (TCRs), termed dual TCR cells, most studies have focused on their autoimmune potential, while their beneficial roles remained elusive. We identified, in normal mice, dual TCR cells that participated in the immune response to a foreign antigen. Unlike single TCR cells, dual TCR cells used the nonselected TCR to respond in the periphery, but relied on coexpression of a second TCR for intrathymic selection. We found that they were selected at low frequency in the naïve repertoire, but dominated the response to antigen through clonal expansion. Thus, dual TCR cells can extend the TCR repertoire for foreign antigens by rescuing functional TCRs that cannot be selected on single TCR cells; they can, therefore, benefit the immune system.

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: The KB TCR cannot mediate intrathymic positive selection of CD4+ T cells.
Figure 2: CD4+ T cells selected through endogenous TCRs express KB TCRs.
Figure 3: Dual TCR cells make up a major part of the selected KB CD4+ T cells.
Figure 4: KB βTg mice have normal CD4+ T cell development and a comparable response to hC4 as B10.S mice.
Figure 5: KB TCRs dominate the hC4-responding repertoire in KB βTg mice.
Figure 6: A large part of the hC4-responding T cells in βTg mice are dual TCR cells.
Figure 7: Measurement of the clonal expansion rate of KB dual TCR cells.

Similar content being viewed by others

References

  1. Burnet, F. M. The clonal selection theory of acquired immunity (Vanderbilt University Press, Nashville, TN, 1959).

    Book  Google Scholar 

  2. Casanova, J. L., Romero, P., Widmann, C., Kourilsky, P. & Maryanski, J. L. T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire. J. Exp. Med. 174, 1371–1383 (1991).

    Article  CAS  Google Scholar 

  3. Padovan, E. et al. Expression of two T cell receptor α chains: dual receptor T cells. Science 262, 422–424 (1993).

    Article  CAS  Google Scholar 

  4. Heath, W. R. et al. Expression of two T cell receptor α chains on the surface of normal murine T cells. Eur. J. Immunol. 25, 1617–1623 (1995).

    Article  CAS  Google Scholar 

  5. Elliott, J. I. Selection of dual Vα T cells. Eur. J. Immunol. 28, 2115–2123 (1998).

    Article  CAS  Google Scholar 

  6. Alam, S. M. & Gascoigne, N. R. Posttranslational regulation of TCR Vα allelic exclusion during T cell differentiation. J. Immunol. 160, 3883–3890 (1998).

    CAS  PubMed  Google Scholar 

  7. Davodeau, F. et al. Dual T cell receptor β chain expression on human T lymphocytes. J. Exp. Med. 181, 1391–1398 (1995).

    Article  CAS  Google Scholar 

  8. Padovan, E. et al. Normal T lymphocytes can express two different T cell receptor β chains: implications for the mechanism of allelic exclusion. J. Exp. Med. 181, 1587–1591 (1995).

    Article  CAS  Google Scholar 

  9. Balomenos, D. et al. Incomplete T cell receptor Vβ allelic exclusion and dual Vβ- expressing cells. J. Immunol. 155, 3308–3312 (1995).

    CAS  PubMed  Google Scholar 

  10. Borgulya, P., Kishi, H., Uematsu, Y. & von Boehmer, H. Exclusion and inclusion of α and β T cell receptor alleles. Cell 69, 529–537 (1992).

    Article  CAS  Google Scholar 

  11. Brandle, D., Muller, C., Rulicke, T., Hengartner, H. & Pircher, H. Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc. Natl Acad. Sci. USA 89, 9529–9533 (1992).

    Article  CAS  Google Scholar 

  12. Kouskoff, V., Vonesch, J. L., Benoist, C. & Mathis, D. The influence of positive selection on RAG expression in thymocytes. Eur. J. Immunol. 25, 54–58 (1995).

    Article  CAS  Google Scholar 

  13. Petrie, H. T. et al. Multiple rearrangements in T cell receptor α chain genes maximize the production of useful thymocytes. J. Exp. Med. 178, 615–622 (1993).

    Article  CAS  Google Scholar 

  14. Padovan, E., Casorati, G., Dellabona, P., Giachino, C. & Lanzavecchia, A. Dual receptor T-cells. Implications for alloreactivity and autoimmunity. Ann. NY Acad. Sci. 756, 66–70 (1995).

    Article  CAS  Google Scholar 

  15. Sarukhan, A., Garcia, C., Lanoue, A. & von Boehmer, H. Allelic inclusion of T cell receptor α genes poses an autoimmune hazard due to low-level expression of autospecific receptors. Immunity 8, 563–570 (1998).

    Article  CAS  Google Scholar 

  16. Zal, T., Weiss, S., Mellor, A. & Stockinger, B. Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. Proc. Natl Acad. Sci. USA 93, 9102–9107 (1996).

    Article  CAS  Google Scholar 

  17. Fossati, G., Cooke, A., Papafio, R. Q., Haskins, K. & Stockinger, B. Triggering a second T cell receptor on diabetogenic T cells can prevent induction of diabetes. J. Exp. Med. 190, 577–583 (1999).

    Article  CAS  Google Scholar 

  18. Elliott, J. I. & Altmann, D. M. Dual T cell receptor α chain T cells in autoimmunity. J. Exp. Med. 182, 953–959 (1995).

    Article  CAS  Google Scholar 

  19. Elliott, J. I. & Altmann, D. M. Nonobese diabetic mice hemizygous at the T cell receptor α locus are susceptible to diabetes and sialitis. Eur. J. Immunol. 26, 953–956 (1996).

    Article  CAS  Google Scholar 

  20. Hardardottir, F., Baron, J. L. & Janeway, C. A. T cells with two functional antigen-specific receptors. Proc. Natl Acad. Sci. USA 92, 354–358 (1995).

    Article  CAS  Google Scholar 

  21. Murray, J. S., Pfeiffer, C., Madri, J. & Bottomly, K. Major histocompatibility complex (MHC) control of CD4 T cell subset activation. II. A single peptide induces either humoral or cell- mediated responses in mice of distinct MHC genotype. Eur. J. Immunol. 22, 559–565 (1992).

    Article  CAS  Google Scholar 

  22. Constant, S. L. & Bottomly, K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15, 297–322 (1997).

    Article  CAS  Google Scholar 

  23. Malissen, B. & Malissen, M. in T cell receptors (eds Bell, J. I., Owen, M. J. & Simpson, E.) 352–365 (Oxford University Press, Oxford, 1995).

    Google Scholar 

  24. Lucas, B. & Germain, R. N. Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. Immunity 5, 461–477 (1996).

    Article  CAS  Google Scholar 

  25. Sant'Angelo, D. B. et al. A molecular map of T cell development. Immunity 9, 179–186 (1998).

    Article  CAS  Google Scholar 

  26. Lyons, A. B. & Parish, C. R. Determination of lymphocyte division by flow cytometry. J. Immunol. Meth. 171, 131–137 (1994).

    Article  CAS  Google Scholar 

  27. Lee, W. T. & Pelletier, W. J. Visualizing memory phenotype development after in vitro stimulation of CD4(+) T cells. Cell. Immunol. 188, 1–11 (1998).

    Article  CAS  Google Scholar 

  28. Suchin, E. J. et al. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J. Immunol. 166, 973–981 (2001).

    Article  CAS  Google Scholar 

  29. Janeway, C. Immunobiology: the immune system in health and disease (Current Biology Publications/Garland Publishers, London & New York, 1999).

    Google Scholar 

  30. Jorgensen, J. L., Esser, U., Fazekas de St. Groth, B., Reay, P. A. & Davis, M. M. Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics. Nature 355, 224–230 (1992).

    Article  CAS  Google Scholar 

  31. Sant'Angelo, D. B. et al. The imprint of intrathymic self-peptides on the mature T cell receptor repertoire. Immunity 7, 517–524 (1997).

    Article  CAS  Google Scholar 

  32. Fukui, Y. et al. Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor β chain. J. Exp. Med. 188, 897–907 (1998).

    Article  CAS  Google Scholar 

  33. Ridgway, W., Fasso, M. & Fathman, C. G. Following antigen challenge, T cells up-regulate cell surface expression of CD4 in vitro and in vivo. J. Immunol. 161, 714–720 (1998).

    CAS  PubMed  Google Scholar 

  34. Mason, D. Allelic exclusion of α chains in TCRs. Int. Immunol. 6, 881–885 (1994).

    Article  CAS  Google Scholar 

  35. Fasso, M. et al. T cell receptor (TCR)-mediated repertoire selection and loss of TCR Vβ diversity during the initiation of a CD4(+) T cell response in vivo. J. Exp. Med. 192, 1719–1730 (2000).

    Article  CAS  Google Scholar 

  36. McHeyzer-Williams, L. J., Panus, J. F., Mikszta, J. A. & McHeyzer-Williams, M. G. Evolution of antigen-specific T cell receptors in vivo: preimmune and antigen-driven selection of preferred complementarity-determining region 3 (CDR3) motifs. J. Exp. Med. 189, 1823–1838 (1999).

    Article  CAS  Google Scholar 

  37. Grubin, C. E., Kovats, S., deRoos, P. & Rudensky, A. Y. Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II-bound self-peptides. Immunity 7, 197–208 (1997).

    Article  CAS  Google Scholar 

  38. Surh, C. D., Lee, D. S., Fung-Leung, W. P., Karlsson, L. & Sprent, J. Thymic selection by a single MHC/peptide ligand produces a semidiverse repertoire of CD4+ T cells. Immunity 7, 209–219 (1997).

    Article  CAS  Google Scholar 

  39. Barton, G. M. & Rudensky, A. Y. Requirement for diverse, low-abundance peptides in positive selection of T cells. Science 283, 67–70 (1999).

    Article  CAS  Google Scholar 

  40. Ignatowicz, L. et al. T cells can be activated by peptides that are unrelated in sequence to their selecting peptide. Immunity 7, 179–186 (1997).

    Article  CAS  Google Scholar 

  41. Kraj, P., Pacholczyk, R. & Ignatowicz, L. αβ TCRs differ in the degree of their specificity for the positively selecting MHC/peptide ligand. J. Immunol. 166, 2251–2259 (2001).

    Article  CAS  Google Scholar 

  42. Kersh, G. J. et al. TCR transgenic mice in which usage of transgenic α- and β-chains is highly dependent on the level of selecting ligand. J. Immunol. 161, 585–593 (1998).

    CAS  PubMed  Google Scholar 

  43. Wong, P., Goldrath, A. W. & Rudensky, A. Y. Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4+ T cell development. J. Immunol. 164, 6252–6259 (2000).

    Article  CAS  Google Scholar 

  44. Simpson, E., Chandler, P., Sponaas, A., Millrain, M. & Dyson, P. J. T cells with dual antigen specificity in T cell receptor transgenic mice rejecting allografts. Eur. J. Immunol. 25, 2813–2817 (1995).

    Article  CAS  Google Scholar 

  45. Lee, W. T., Shiledar-Baxi, V., Winslow, G. M., Mix, D. & Murphy, D. B. Self-restricted dual receptor memory T cells. J. Immunol. 161, 4513–4519 (1998).

    CAS  PubMed  Google Scholar 

  46. Kouskoff, V., Signorelli, K., Benoist, C. & Mathis, D. Cassette vectors directing expression of T cell receptor genes in transgenic mice. J. Immunol. Meth. 180, 273–280 (1995).

    Article  CAS  Google Scholar 

  47. Harrington, C. J. et al. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. Immunity 8, 571–580 (1998).

    Article  CAS  Google Scholar 

  48. Viret, C., Lantz, O., He, X., Bendelac, A. & Janeway, C. A. A NK1.1+ thymocyte-derived TCR β-chain transgene promotes positive selection of thymic NK1.1+ α β T cells. J. Immunol. 165, 3004–3014 (2000).

    Article  CAS  Google Scholar 

  49. Viret, C., Wong, F. S. & Janeway, C. A. Jr Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition. Immunity 10, 559–568 (1999).

    Article  CAS  Google Scholar 

  50. Sant'Angelo, D. B. et al. The specificity and orientation of a TCR to its peptide-MHC class II ligands. Immunity 4, 367–376 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Crispe for critical comments on the manuscript; D. Sant'Angelo for advice; G. Losyev for help on screening mice; D. Mathis and C. Benoist for pTα and pTβ cassette vectors. Supported in part by NIH grants (AI-26791, CA-28250 to K. B., and AI-14579 to C. J.), and by the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, 310 Cedar St., New Haven, 06520-8011, CT, USA

    Xin He, Charles A. Janeway Jr., Matthew Levine, Eve Robinson, Paula Preston-Hurlburt, Christophe Viret & Kim Bottomly

  2. The Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar St., New Haven, 06520-8011, CT, USA

    Charles A. Janeway Jr. & Eve Robinson

Authors
  1. Xin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles A. Janeway Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eve Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paula Preston-Hurlburt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christophe Viret
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kim Bottomly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xin He.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Web Figure 1.

KB TCR is not positively selected in the αTg×KB RAG-1−/− thymus. The αTg was derived from the T cell hybrid T200.4E. The αTg×KB RAG-1−/− thymus was from mice that expressed both the αTg and the KB αβTCR on the RAG-1−/− background. Coexpression of the second αTg will reduce the expression level of KB TCR. We found no positive selection in the thymus: lack of CD4 single positive T cells (<1%); no mature CD4+ cells (<1%) in Vβ8hi-gated post-selection thymocytes; and a normal number of total thymocytes (75×106 cells) with majority being the immature CD4+CD8+ cells (82%). CD4 and CD8 distributions are shown as a dot-plot without (left) and with (right) electronic gating on Vβ8hi thymocytes. The expression of the KB TCRβ chain (Vβ8) is shown as a histogram. Single-cell suspensions of the thymus were triple stained for CD4, CD8 and Vβ8. The profiles are representative of two experiments. (GIF 16 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, X., Janeway, C., Levine, M. et al. Dual receptor T cells extend the immune repertoire for foreign antigens. Nat Immunol 3, 127–134 (2002). https://doi.org/10.1038/ni751

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni751

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing