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.

  • Research Article
  • Published:

The interaction of influenza H5N1 viral hemagglutinin with sialic acid receptors leads to the activation of human γδ T cells

Cellular & Molecular Immunology volume 10, pages 463–470 (2013)Cite this article

Abstract

Highly pathogenic avian influenza H5N1 epidemics are a significant public health hazard. Genetically engineered H5N1 viruses with mammalian transmission activity highlight the potential risk of a human influenza H5N1 pandemic. Understanding the underlying principles of the innate immune system in response to influenza H5N1 viruses will lead to improved prevention and control of these potentially deadly viruses. γδ T cells act as the first line of defense against microbial infection and help initiate adaptive immune responses during the early stages of viral infection. In this study, we investigated the molecular mechanisms of γδ T cells in response to influenza H5N1 viral infection. We found that recombinant hemagglutinin (rHA) derived from three different strains of influenza H5N1 viruses elicited the activation of γδ T cells cultured in peripheral blood mononuclear cells (PBMCs). Both the cell surface expression of CD69, an early activation marker on γδ T cells, and the production of interferon-γ (IFN-γ) were significantly increased. Notably, the rHA protein-induced γδ T-cell activation was not mediated by TCRγδ, NKG2D or pattern recognition receptors (PRRs) or NKp46 receptors. The interaction of rHA proteins with sialic acid receptors may play a critical role in γδ T-cell activation. Our data may provide insight into the mechanisms underlying γδ T-cell activation in response to infection with H5N1 viruses.

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

Similar content being viewed by others

References

  1. CDC. Update: Influenza activity-United States and worldwide, 2006–07 season, and composition of the 2007–08 influenza vaccine. MMWR Morb Mortal Wkly Rep 2007; 56: 789–794.

    Google Scholar 

  2. WHO. Cumulative Number of Confirmed Human Cases for Avian Influenza A(H5N1) Reported to WHO, 2003–2012. Geneva: WHO, 2012.

  3. WHO. Update on human cases of highly pathogenic avian influenza A(H5N1) virus infection, 2011. Wkly Epidemiol Rec 2012; 13: 117–128.

    Google Scholar 

  4. Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 2012; 336: 1534–1541.

    Article  CAS  PubMed Central  Google Scholar 

  5. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 2012; 486: 420–428.

    Article  CAS  PubMed Central  Google Scholar 

  6. Morens DM, Subbarao K, Taubenberger JK . Engineering H5N1 avian influenza viruses to study human adaptation. Nature 2012; 486: 335–340.

    Article  CAS  PubMed Central  Google Scholar 

  7. Inglesby TV, Cicero A, Henderson DA . The risk of engineering a highly transmissible H5N1 virus. Biosecur Bioterror 2012; 10: 151–152.

    Article  Google Scholar 

  8. Taubenberger JK, Kash JC . Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 2010; 7: 440–451.

    Article  CAS  PubMed Central  Google Scholar 

  9. Du L, Jin L, Zhao G, Sun S, Li J, Yu H et al. Identification and structural characterization of a broadly neutralizing antibody targeting a novel conserved epitope on influenza H5N1 hemagglutinin. J Virol 2013; 87: 2215–2225.

    Article  CAS  PubMed Central  Google Scholar 

  10. Qian M, Hu H, Zuo T, Wang G, Zhang L, Zhou P . Unravel a neutralization mechanism by two human antibodies against conserved epitopes in the globular head of H5 hemagglutinin. J Virol 2013; 87: 3571–3577.

    Article  CAS  PubMed Central  Google Scholar 

  11. Wang X, Chan CC, Yang M, Deng J, Poon VK, Leung VH et al. A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection. Cell Mol Immunol 2011; 8: 462–468.

    Article  CAS  PubMed Central  Google Scholar 

  12. Bonneville M, Scotet E . Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 2006; 18: 539–546.

    Article  CAS  Google Scholar 

  13. Born WK, Reardon CL, O'Brien RL . The function of gammadelta T cells in innate immunity. Curr Opin Immunol 2006; 18: 31–38.

    Article  CAS  Google Scholar 

  14. Zheng J, Liu Y, Lau YL, Tu W . gammadelta-T cells: an unpolished sword in human anti-infection immunity. Cell Mol Immunol 2013; 10: 50–57.

    Article  CAS  Google Scholar 

  15. Qin G, Liu Y, Zheng J, Ng IH, Xiang Z, Lam KT et al. Type 1 responses of human Vgamma9Vdelta2 T cells to influenza A viruses. J Virol 2011; 85: 10109–10116.

    Article  CAS  PubMed Central  Google Scholar 

  16. Qin G, Mao H, Zheng J, Sia SF, Liu Y, Chan PL et al. Phosphoantigen-expanded human gammadelta T cells display potent cytotoxicity against monocyte-derived macrophages infected with human and avian influenza viruses. J Infect Dis 2009; 200: 858–865.

    Article  CAS  Google Scholar 

  17. Jameson JM, Cruz J, Costanzo A, Terajima M, Ennis FA . A role for the mevalonate pathway in the induction of subtype cross-reactive immunity to influenza A virus by human gammadelta T lymphocytes. Cell Immunol 2010; 264: 71–77.

    Article  CAS  PubMed Central  Google Scholar 

  18. Li Z, Liu Z, Ma C, Zhang L, Su Y, Gao GF et al. Identification of amino acids in highly pathogenic avian influenza H5N1 virus hemagglutinin that determine avian influenza species specificity. Arch Virol 2011; 156: 1803–1812.

    Article  CAS  Google Scholar 

  19. Li Z, Ma C, Liu Z, He W . Serologic cross-reactivity among humans and birds infected with highly pathogenic avian influenza A subtype H5N1 viruses in China. Immunol Lett 2011; 135: 59–63.

    Article  CAS  Google Scholar 

  20. Li X, Kang N, Zhang X, Dong X, Wei W, Cui L et al. Generation of human regulatory gammadelta T cells by TCRgammadelta stimulation in the presence of TGF-beta and their involvement in the pathogenesis of systemic lupus erythematosus. J Immunol 2011; 186: 6693–6700.

    Article  CAS  Google Scholar 

  21. Terajima M, Cruz J, Co MD, Lee JH, Kaur K, Wrammert J et al. Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies. J Virol 2011; 85: 13463–13467.

    Article  CAS  PubMed Central  Google Scholar 

  22. Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 2011; 208: 181–193.

    Article  CAS  PubMed Central  Google Scholar 

  23. Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009; 325: 197–201.

    Article  CAS  PubMed Central  Google Scholar 

  24. Cao W, He W . The recognition pattern of gammadelta T cells. Front Biosci 2005; 10: 2676–2700.

    Article  CAS  Google Scholar 

  25. Du N, Zhou J, Lin X, Zhang Y, Yang X, Wang Y et al. Differential activation of NK cells by influenza A pseudotype H5N1 and 1918 and 2009 pandemic H1N1 viruses. J Virol 2010; 84: 7822–7831.

    Article  CAS  PubMed Central  Google Scholar 

  26. Kabelitz D, He W . The multifunctionality of human Vgamma9Vdelta2 gammadelta T cells: clonal plasticity or distinct subsets? Scand J Immunol 2012; 76: 213–222.

    Article  CAS  Google Scholar 

  27. Kabelitz D, Wesch D, He W . Perspectives of gammadelta T cells in tumor immunology. Cancer Res 2007; 67: 5–8.

    Article  CAS  Google Scholar 

  28. Chen ZW . Multifunctional immune responses of HMBPP-specific Vgamma2Vdelta2 T cells in M. tuberculosis and other infections. Cell Mol Immunol 2013; 10: 58–64.

    Article  Google Scholar 

  29. Fournie JJ, Sicard H, Poupot M, Bezombes C, Blanc A, Romagne F et al. What lessons can be learned from gammadelta T cell-based cancer immunotherapy trials? Cell Mol Immunol 2013; 10: 35–41.

    Article  CAS  Google Scholar 

  30. Caccamo N, Todaro M, Sireci G, Meraviglia S, Stassi G, Dieli F . Mechanisms underlying lineage commitment and plasticity of human gammadelta T cells. Cell Mol Immunol 2013; 10: 30–34.

    Article  CAS  Google Scholar 

  31. Born WK, Kemal Aydintug M, O'Brien RL . Diversity of gammadelta T-cell antigens. Cell Mol Immunol 2013; 10: 13–20.

    Article  CAS  Google Scholar 

  32. Kabelitz D, Wesch D, Hinz T . gamma delta T cells, their T cell receptor usage and role in human diseases. Springer Semin Immunopathol 1999; 21: 55–75.

    CAS  PubMed  Google Scholar 

  33. Li H, Lebedeva MI, Llera AS, Fields BA, Brenner MB, Mariuzza RA . Structure of the Vdelta domain of a human gammadelta T-cell antigen receptor. Nature 1998; 391: 502–506.

    Article  CAS  Google Scholar 

  34. Rock EP, Sibbald PR, Davis MM, Chien YH . CDR3 length in antigen-specific immune receptors. J Exp Med 1994; 179: 323–328.

    Article  CAS  Google Scholar 

  35. Allison TJ, Winter CC, Fournie JJ, Bonneville M, Garboczi DN . Structure of a human gammadelta T-cell antigen receptor. Nature 2001; 411: 820–824.

    Article  CAS  Google Scholar 

  36. Xi X, Cui L, He W . The recognition of gammadelta TCR to protein antigen does not depend on the hydrophobic I97 residue of CDR3delta. Int Immunol 2010; 22: 299–306.

    Article  CAS  Google Scholar 

  37. Wang Z, Zhang T, Hu H, Zhang H, Yang Z, Cui L et al. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody. Cancer Lett 2008; 272: 242–252.

    Article  CAS  Google Scholar 

  38. Nedellec S, Sabourin C, Bonneville M, Scotet E . NKG2D costimulates human V gamma 9V delta 2 T cell antitumor cytotoxicity through protein kinase C theta-dependent modulation of early TCR-induced calcium and transduction signals. J Immunol 2010; 185: 55–63.

    Article  CAS  Google Scholar 

  39. Suzuki T, Terao S, Acharya B, Naoe M, Yamamoto S, Okamura H et al. The antitumour effect of {gamma}{delta} T-cells is enhanced by valproic acid-induced up-regulation of NKG2D ligands. Anticancer Res 2010; 30: 4509–4513.

    CAS  PubMed  Google Scholar 

  40. Kuroda H, Saito H, Ikeguchi M . Decreased number and reduced NKG2D expression of Vdelta1 gammadelta T cells are involved in the impaired function of Vdelta1 gammadelta T cells in the tissue of gastric cancer. Gastric Cancer 2012; 15: 433–439.

    Article  CAS  Google Scholar 

  41. Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T . Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 2005; 175: 2144–2151.

    Article  CAS  Google Scholar 

  42. Zhou J, Kang N, Cui L, Ba D, He W . Anti-gammadelta TCR antibody-expanded gammadelta T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies. Cell Mol Immunol 2012; 9: 34–44.

    Article  CAS  Google Scholar 

  43. Maris NA, Dessing MC, de Vos AF, Bresser P, van der Zee JS, Jansen HM et al. Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin. Eur Rrespir J 2006; 28: 622–626.

    Article  CAS  Google Scholar 

  44. Kovach MA, Standiford TJ . Toll like receptors in diseases of the lung. Int Immunopharmacol 2011; 11: 1399–1406.

    Article  CAS  PubMed Central  Google Scholar 

  45. Ramos I, Fernandez-Sesma A . Innate immunity to H5N1 influenza viruses in humans. Viruses 2012; 4: 3363–3388.

    Article  CAS  PubMed Central  Google Scholar 

  46. Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 2001; 409: 1055–1060.

    Article  CAS  Google Scholar 

  47. Oshansky CM, Pickens JA, Bradley KC, Jones LP, Saavedra-Ebner GM, Barber JP et al. Avian influenza viruses infect primary human bronchial epithelial cells unconstrained by sialic acid alpha2,3 residues. PloS ONE 2011; 6: e21183.

    Article  CAS  PubMed Central  Google Scholar 

  48. Springer GF, Schwick HG, Fletcher MA . The relationship of the influenza virus inhibitory activity of glycoproteins to their molecular size and sialic acid content. Proc Natl Acad Sci USA 1969; 64: 634–641.

    Article  CAS  Google Scholar 

  49. Weis W, Brown JH, Cusack S, Paulson JC, Skehel JJ, Wiley DC . Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature 1988; 333: 426–431.

    Article  CAS  Google Scholar 

  50. Ruigrok RW, Aitken A, Calder LJ, Martin SR, Skehel JJ, Wharton SA et al. Studies on the structure of the influenza virus haemagglutinin at the pH of membrane fusion. J Gen Virol 1988; 69( Pt 11): 2785–2795.

    Article  CAS  Google Scholar 

  51. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD et al. H5N1 virus attachment to lower respiratory tract. Science 2006; 312: 399.

    Article  CAS  Google Scholar 

  52. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y . Avian flu: influenza virus receptors in the human airway. Nature 2006; 440: 435–436.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by two grants, No. CHB1-31056-BE-11 from the US Civilian Research & Development Foundation from the National Institute of Allergy and Infectious Diseases and No. 31070785 from the National Natural Science Foundation of China. We thank Dr Jianmin Zhang and Dr Austin Cape for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China

    Yanlai Lu, Zhen Li, Chi Ma, Hao Wang, Jing Zheng, Lianxian Cui & Wei He

Authors
  1. Yanlai Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lianxian Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, Y., Li, Z., Ma, C. et al. The interaction of influenza H5N1 viral hemagglutinin with sialic acid receptors leads to the activation of human γδ T cells. Cell Mol Immunol 10, 463–470 (2013). https://doi.org/10.1038/cmi.2013.26

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2013.26

Keywords

Search

Advanced search

Quick links