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Antigen-specific NK cell memory in rhesus macaques

Nature Immunology volume 16, pages 927–932 (2015)Cite this article

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Abstract

Natural killer (NK) cells have traditionally been considered nonspecific components of innate immunity, but recent studies have shown features of antigen-specific memory in mouse NK cells. However, it has remained unclear whether this phenomenon also exists in primates. We found that splenic and hepatic NK cells from SHIVSF162P3-infected and SIVmac251-infected macaques specifically lysed Gag- and Env-pulsed dendritic cells in an NKG2-dependent fashion, in contrast to NK cells from uninfected macaques. Moreover, splenic and hepatic NK cells from Ad26-vaccinated macaques efficiently lysed antigen-matched but not antigen-mismatched targets 5 years after vaccination. These data demonstrate that robust, durable, antigen-specific NK cell memory can be induced in primates after both infection and vaccination, and this finding could be important for the development of vaccines against HIV-1 and other pathogens.

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Figure 1: Purification of macaque NK cells.
Figure 2: Antigen-specific lysis of autologous DCs by NK cells in chronically SHIVSF162P3-infected macaques.
Figure 3: Antigen-specific NK cell responses in SIVmac251-infected macaques.
Figure 4: Antigen-specific NK cell memory in vaccinated macaques.
Figure 5: Antigen-specific NK cell killing is dependent on NKG2A and NKG2C.

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References

  1. Alpert, M.D. et al. ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge. PLoS Pathog. 8, e1002890 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Banks, N.D., Kinsey, N., Clements, J. & Hildreth, J.E. Sustained antibody-dependent cell-mediated cytotoxicity (ADCC) in SIV-infected macaques correlates with delayed progression to AIDS. AIDS Res. Hum. Retroviruses 18, 1197–1205 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Johansson, S.E. et al. NK cell function and antibodies mediating ADCC in HIV-1-infected viremic and controller patients. Viral Immunol. 24, 359–368 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Waggoner, S.N., Cornberg, M., Selin, L.K. & Welsh, R.M. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481, 394–398 (2012).

    Article  CAS  Google Scholar 

  5. Soderquest, K. et al. Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. J. Immunol. 186, 3304–3308 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Lang, P.A. et al. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc. Natl. Acad. Sci. USA 109, 1210–1215 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Alter, G. et al. Evolution of innate and adaptive effector cell functions during acute HIV-1 infection. J. Infect. Dis. 195, 1452–1460 (2007).

    Article  PubMed  CAS  Google Scholar 

  8. Bandyopadhyay, S. et al. Natural killer cell-mediated lysis of T cell lines chronically infected with HIV-1. Clin. Exp. Immunol. 79, 430–435 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bonaparte, M.I. & Barker, E. Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood 104, 2087–2094 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Ward, J. et al. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 110, 1207–1214 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fehniger, T.A. et al. Natural killer cells from HIV-1+ patients produce C–C chemokines and inhibit HIV-1 infection. J. Immunol. 161, 6433–6438 (1998).

    CAS  PubMed  Google Scholar 

  12. Shieh, T.M. et al. Functional analyses of natural killer cells in macaques infected with neurovirulent simian immunodeficiency virus. J. Neurovirol. 7, 11–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Vowels, B.R., Gershwin, M.E., Gardner, M.B. & McGraw, T.P. Natural killer cell activity of rhesus macaques against retrovirus-pulsed CD4+ target cells. AIDS Res. Hum. Retroviruses 6, 905–918 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Giavedoni, L.D., Velasquillo, M.C., Parodi, L.M., Hubbard, G.B. & Hodara, V.L. Cytokine expression, natural killer cell activation, and phenotypic changes in lymphoid cells from rhesus macaques during acute infection with pathogenic simian immunodeficiency virus. J. Virol. 74, 1648–1657 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takahashi, Y. et al. In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection. PLoS Pathog. 10, e1003929 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Bostik, P. et al. Decreased NK cell frequency and function is associated with increased risk of KIR3DL allele polymorphism in simian immunodeficiency virus-infected rhesus macaques with high viral loads. J. Immunol. 182, 3638–3649 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Rouzaire, P. et al. Natural killer cells and T cells induce different types of skin reactions during recall responses to haptens. Eur. J. Immunol. 42, 80–88 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Majewska-Szczepanik, M., Paust, S., von Andrian, U.H., Askenase, P.W. & Szczepanik, M. Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-α, interferon-γ and interleukin-12. Immunology 140, 98–110 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell–mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paust, S. & von Andrian, U.H. Natural killer cell memory. Nat. Immunol. 12, 500–508 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. O'Leary, J.G., Goodarzi, M., Drayton, D.L. & von Andrian, U.H. T cell– and B cell–independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 7, 507–516 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gillard, G.O. et al. Thy1+ NK [corrected] cells from vaccinia virus-primed mice confer protection against vaccinia virus challenge in the absence of adaptive lymphocytes. PLoS Pathog. 7, e1002141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gazit, R. et al. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat. Immunol. 7, 517–523 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Smith, H.R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99, 8826–8831 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fang, M. et al. CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 34, 579–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun, J.C., Beilke, J.N. & Lanier, L.L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ravet, S. et al. Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals. Blood 109, 4296–4305 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Scott-Algara, D. et al. Cutting edge: increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users. J. Immunol. 171, 5663–5667 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Tiemessen, C.T. et al. Cutting edge: unusual NK cell responses to HIV-1 peptides are associated with protection against maternal-infant transmission of HIV-1. J. Immunol. 182, 5914–5918 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Alter, G. et al. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476, 96–100 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lopez-Vergès, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl. Acad. Sci. USA 108, 14725–14732 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Eisenhardt, M. et al. CD27(+)CD56Bright natural killer cells may be involved in spontaneous clearance of acute hepatitis C in HIV-positive patients. AIDS 28, 1879–1884 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Reeves, R.K. et al. CD16− natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection. Blood 115, 4439–4446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shang, L. et al. NK cell responses to simian immunodeficiency virus vaginal exposure in naive and vaccinated rhesus macaques. J. Immunol. 193, 277–284 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Robinette, M.L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Barouch, D.H. et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 482, 89–93 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Flores-Villanueva, P.O. et al. Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc. Natl. Acad. Sci. USA 98, 5140–5145 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Alter, G. et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027–3036 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, T., Scott, J.M., Hwang, I. & Kim, S. Cutting edge: antibody-dependent memory-like NK cells distinguished by FcRγ deficiency. J. Immunol. 190, 1402–1406 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Lee, J. et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42, 431–442 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Thomas, R. et al. NKG2C deletion is a risk factor of HIV infection. AIDS Res. Hum. Retroviruses 28, 844–851 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Marras, F. et al. Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation. Proc. Natl. Acad. Sci. USA 110, 11970–11975 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. O'Connell, K.A., Han, Y., Williams, T.M., Siliciano, R.F. & Blankson, J.N. Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. J. Virol. 83, 5028–5034 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Choi, E.I., Reimann, K.A. & Letvin, N.L. In vivo natural killer cell depletion during primary simian immunodeficiency virus infection in rhesus monkeys. J. Virol. 82, 6758–6761 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Moreland, A.J. et al. Characterization of killer immunoglobulin-like receptor genetics and comprehensive genotyping by pyrosequencing in rhesus macaques. BMC Genomics 12, 295 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health (grants AI078526, AI096040 and AI095985 to D.H.B.; AI069259, AI111595 and AI112521 to U.H.v.A.; AI067031 to M.A.; and AI118468 to R.K.R.), the American Foundation for AIDS Research (grant 108547-53-RGRL to R.K.R.), the Harvard Center for AIDS Research (grant AI060354 to R.K.R.) and the Ragon Institute of MGH, MIT and Harvard (S.J., M.A., D.H.B. and U.H.v.A.).

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Authors and Affiliations

  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    R Keith Reeves, Haiying Li, Eryn Blass, Hualin Li, Jamie L Schafer, Valerie Varner, Cordelia Manickam, Leila Eslamizar & Dan H Barouch

  2. Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA

    R Keith Reeves & Haiying Li

  3. Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, Massachusetts, USA

    Stephanie Jost, Marcus Altfeld, Ulrich H von Andrian & Dan H Barouch

  4. Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany

    Marcus Altfeld

  5. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA

    Ulrich H von Andrian

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Contributions

R.K.R., M.A., U.H.v.A. and D.H.B. designed the studies. Haiying Li, S.J., E.B., Hualin Li, J.L.S., V.V., C.M. and L.E. conducted the assays. R.K.R. and D.H.B. wrote the paper with the assistance of all other authors.

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Correspondence to R Keith Reeves or Dan H Barouch.

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Reeves, R., Li, H., Jost, S. et al. Antigen-specific NK cell memory in rhesus macaques. Nat Immunol 16, 927–932 (2015). https://doi.org/10.1038/ni.3227

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