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:

A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy

Nature Chemical Biology volume 10, pages 943–949 (2014)Cite this article

Subjects

Abstract

Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer–like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Assessment of the glycolipid scaffold for vaccine design.
Figure 2: Structure and in vivo activity of a prodrug agonist of NKT cells.
Figure 3: Conjugated peptide vaccines stimulate potent CD8+ T cell–mediated immune responses.
Figure 4: Conjugated peptide vaccines stimulate NKT cells.
Figure 5: Allergen-specific conjugate vaccines reduce allergic airway inflammation in sensitized animals without affecting serum IgE levels.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Janeway, C.A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Steinman, R.M. & Banchereau, J. Taking dendritic cells into medicine. Nature 449, 419–426 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Jackson, D.C. et al. A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses. Proc. Natl. Acad. Sci. USA 101, 15440–15445 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Khan, S. et al. Distinct uptake mechanisms but similar intracellular processing of two different toll-like receptor ligand-peptide conjugates in dendritic cells. J. Biol. Chem. 282, 21145–21159 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Oh, J.Z. & Kedl, R.M. The capacity to induce cross-presentation dictates the success of a TLR7 agonist-conjugate vaccine for eliciting cellular immunity. J. Immunol. 185, 4602–4608 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Ingale, S., Wolfert, M.A., Gaekwad, J., Buskas, T. & Boons, G.J. Robust immune responses elicited by a fully synthetic three-component vaccine. Nat. Chem. Biol. 3, 663–667 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tighe, H. et al. Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur. J. Immunol. 30, 1939–1947 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Vecchi, S. et al. Conjugation of a TLR7 agonist and antigen enhances protection in the S. pneumoniae murine infection model. Eur. J. Pharm. Biopharm. 87, 310–317 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R. & Melief, C.J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Hunn, M.K. & Hermans, I.F. Exploiting invariant NKT cells to promote T-cell responses to cancer vaccines. Oncoimmunology 2, e23789 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arase, H., Arase, N., Ogasawara, K., Good, R.A. & Onoé, K. An NK1.1+ CD4+8− single-positive thymocyte subpopulation that expresses a highly skewed T-cell antigen receptor V β family. Proc. Natl. Acad. Sci. USA 89, 6506–6510 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lantz, O. & Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8− T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Fujii, S., Shimizu, K., Smith, C., Bonifaz, L. & Steinman, R.M. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198, 267–279 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gonzalez-Aseguinolaza, G. et al. Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines. J. Exp. Med. 195, 617–624 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hermans, I.F. et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J. Immunol. 171, 5140–5147 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Stober, D., Jomantaite, I., Schirmbeck, R. & Reimann, J. NKT cells provide help for dendritic cell-dependent priming of MHC class I–restricted CD8+ T cells in vivo. J. Immunol. 170, 2540–2548 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Semmling, V. et al. Alternative cross-priming through CCL17–CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat. Immunol. 11, 313–320 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. van Rijt, L.S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Enomoto, N. et al. Allergen-specific CTL require perforin expression to suppress allergic airway inflammation. J. Immunol. 188, 1734–1741 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Aguilar-Pimentel, J.A. et al. Specific CD8 T cells in IgE-mediated allergy correlate with allergen dose and allergic phenotype. Am. J. Respir. Crit. Care Med. 181, 7–16 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Wells, J.W., Cowled, C.J., Giorgini, A., Kemeny, D.M. & Noble, A. Regulation of allergic airway inflammation by class I–restricted allergen presentation and CD8 T-cell infiltration. J. Allergy Clin. Immunol. 119, 226–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Pellicci, D.G. et al. Differential recognition of CD1d-α-galactosylceramide by the Vβ8.2 and Vβ7 semi-invariant NKT T cell receptors. Immunity 31, 47–59 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alexander, J., Cargill, R., Michelson, S.R. & Schwam, H. (Acyloxy)alkyl carbamates as novel bioreversible prodrugs for amines: increased permeation through biological membranes. J. Med. Chem. 31, 318–322 (1988).

    Article  CAS  PubMed  Google Scholar 

  28. Flechtner, J.B. et al. High-affinity interactions between peptides and heat shock protein 70 augment CD8+ T lymphocyte immune responses. J. Immunol. 177, 1017–1027 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Bendelac, A., Savage, P.B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Farrand, K.J. et al. Langerin+ CD8α+ dendritic cells are critical for cross-priming and IL-12 production in response to systemic antigens. J. Immunol. 183, 7732–7742 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Mustapa, M.F.M. et al. Stabilized integrin-targeting ternary LPD (lipopolyplex) vectors for gene delivery designed to disassemble within the target cell. Bioconjug. Chem. 20, 518–532 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Elewaut, D. et al. The adaptor protein AP-3 is required for CD1d-mediated antigen presentation of glycosphingolipids and development of Vα14i NKT cells. J. Exp. Med. 198, 1133–1146 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. van den Elzen, P. et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437, 906–910 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Freigang, S. et al. Scavenger receptors target glycolipids for natural killer T cell activation. J. Clin. Invest. 122, 3943–3954 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kitamura, H. et al. α-Galactosylceramide induces early B-cell activation through IL-4 production by NKT cells. Cell. Immunol. 199, 37–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Galli, G. et al. CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J. Exp. Med. 197, 1051–1057 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lang, G.A., Exley, M.A. & Lang, M.L. The CD1d-binding glycolipid α-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology 119, 116–125 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Miyahara, N. et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat. Med. 10, 865–869 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Erard, F., Wild, M.T., Garcia-Sanz, J.A. & Le Gros, G. Switch of CD8 T cells to noncytolytic CD8− CD4− cells that make TH2 cytokines and help B cells. Science 260, 1802–1805 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Cui, J. et al. Inhibition of T helper cell type 2 cell differentiation and immunoglobulin E response by ligand-activated Vα14 natural killer T cells. J. Exp. Med. 190, 783–792 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hachem, P. et al. α-Galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role of IFN-γ. Eur. J. Immunol. 35, 2793–2802 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Matsuda, H. et al. α-Galactosylceramide, a ligand of natural killer T cells, inhibits allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 33, 22–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Morishima, Y. et al. Suppression of eosinophilic airway inflammation by treatment with α-galactosylceramide. Eur. J. Immunol. 35, 2803–2814 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Kim, J.-O. et al. Asthma is induced by intranasal coadministration of allergen and natural killer T-cell ligand in a mouse model. J. Allergy Clin. Immunol. 114, 1332–1338 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Meyer, E.H. et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc. Natl. Acad. Sci. USA 103, 2782–2787 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Parekh, V.V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Invest. 115, 2572–2583 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee, A. et al. Novel synthesis of α-galactosylceramides and confirmation of their powerful NKT cell agonist activity. Carbohydr. Res. 341, 2785–2798 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Pircher, H., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R.M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

    Article  CAS  PubMed  Google Scholar 

  50. Köntgen, F., Suss, G., Stewart, C., Steinmetz, M. & Bluethmann, H. Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. Int. Immunol. 5, 957–964 (1993).

    Article  PubMed  Google Scholar 

  51. Chen, Y.H., Chiu, N.M., Mandal, M., Wang, N. & Wang, C.R. Impaired NK1+ T cell development and early IL-4 production in CD1-deficient mice. Immunity 6, 459–467 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Giaccone, G. et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin. Cancer Res. 8, 3702–3709 (2002).

    CAS  PubMed  Google Scholar 

  54. Zajonc, D.M. et al. Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor. Nat. Immunol. 6, 810–818 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Watson, J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J. Exp. Med. 150, 1510–1519 (1979).

    Article  CAS  PubMed  Google Scholar 

  57. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat. Immunol. 14, 564–573 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the personnel of the Biomedical Research Unit of the Malaghan Institute of Medical Research for animal husbandry, K. Price for flow cytometry support, and the US National Institutes of Health Tetramer Core Facility (contract HHSN272201300006C) for provision of CD1d monomers. This research was supported by the New Zealand Ministry of Science and Innovation (C08X0808) and a research grant from the New Zealand Health Research Council to F.R. N.J.D. was supported by the Rotary Club of Wellington and the University of Otago.

Author information

Author notes

  1. Regan J Anderson and Ching-wen Tang: These authors contributed equally to this work.

Authors and Affiliations

  1. The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand

    Regan J Anderson, Benjamin J Compton, Colin M Hayman, Karen A Johnston & Gavin F Painter

  2. Malaghan Institute of Medical Research, Wellington, New Zealand

    Ching-wen Tang, Naomi J Daniels, Deborah A Knight, Olivier Gasser, Hazel C Poyntz, Franca Ronchese & Ian F Hermans

  3. Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand

    Naomi J Daniels

  4. Capital and Coast District Health Board, Wellington, New Zealand

    Peter M Ferguson

  5. Department of Chemistry, University of Otago, Dunedin, New Zealand

    David S Larsen

  6. School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand

    Ian F Hermans

Authors
  1. Regan J Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ching-wen Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naomi J Daniels
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benjamin J Compton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Colin M Hayman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen A Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Deborah A Knight
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Olivier Gasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hazel C Poyntz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Peter M Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David S Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Franca Ronchese
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gavin F Painter
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ian F Hermans
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.F.H. and G.F.P. led the investigation together, contributed to design of conjugates, designed in vivo experiments and interpreted data; R.J.A. was primarily responsible for design, synthesis and chemical analysis of the conjugates, with contributions from B.J.C., C.M.H., K.A.J. and D.S.L.; C.T. was primarily responsible for in vivo analysis of conjugates, with contributions from D.A.K.; O.G. conducted in vitro assessment of conjugates; N.J.D. performed allergic airway experiments with contributions from H.C.P.; K.A.J. conducted molecular modeling; F.R. led analysis of airway inflammation; P.M.F. reviewed histology; I.F.H. drafted the manuscript with editorial input from all authors.

Corresponding authors

Correspondence to Gavin F Painter or Ian F Hermans.

Ethics declarations

Competing interests

Two PCT applications have been filed with the Intellectual Property Office of New Zealand: application no. NZ2013/000224 (with G.F.P., R.J.A., B.J.C., C.M.H, I.F.H., F.R. and D.S.L), filed 6 December 2013, and no. NZ2013/000133 (G.F.P., R.J.A., B.J.C., C.M.H, I.F.H. and D.S.L), filed 26 July 2013. These applications encompass a-GalCer peptide conjugates and prodrugs, such as compounds 4 and 5 described in this work. The intellectual property is assigned to VicLink, Victoria University of Wellington.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–8 and Supplementary Table 1. (PDF 5997 kb)

Supplementary Note

Supplementary Note, Supplementary Figures 9–15 (PDF 1282 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Anderson, R., Tang, Cw., Daniels, N. et al. A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy. Nat Chem Biol 10, 943–949 (2014). https://doi.org/10.1038/nchembio.1640

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1640

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