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Natural killer cell specificity for viral infections

Nature Immunology volume 19, pages 800–808 (2018)Cite this article

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Abstract

Natural killer (NK) cells are lymphocytes that contribute to the early immune responses to viruses. NK cells are innate immune cells that do not express rearranged antigen receptors but sense their environment via receptors for pro-inflammatory cytokines, as well as via germline-encoded activating receptors specific for danger or pathogen signals. A group of such activating receptors is stochastically expressed by certain subsets within the NK cell compartment. After engagement of the cognate viral ligand, these receptors contribute to the specific activation and ‘preferential’ population expansion of defined NK cell subsets, which partially recapitulate some features of adaptive lymphocytes. In this Review, we discuss the numerous modes for the specific recognition of viral antigens and peptides by NK cells and the implications of this for the composition of the NK cell repertoire as well as for the the selection of viral variants.

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Fig. 1: Modes of NK cell recognition during viral infection.
Fig. 2: Consequences of the specific recognition of viral antigens.
Fig. 3: Innate receptor–mediated immunological pressure potentially favors viral strains on the basis of ligand strength.
Fig. 4: Peptide-specific recognition of viral infection via receptors of the KIR and NKG2 families.

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References

  1. Kiessling, R., Klein, E. & Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5, 112–117 (1975).

    CAS  PubMed  Google Scholar 

  2. Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).

    CAS  PubMed  Google Scholar 

  3. Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–678 (1986).

    PubMed  Google Scholar 

  4. Kärre, K. Natural killer cell recognition of missing self. Nat. Immunol. 9, 477–480 (2008).

    PubMed  Google Scholar 

  5. Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).

    CAS  PubMed  Google Scholar 

  6. Björkström, N. K. et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 116, 3853–3864 (2010).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hammer, Q., Rückert, T., Dunst, J. & Romagnani, C. Adaptive natural killer cells integrate interleukin-18 during target-cell encounter. Front. Immunol. 8, 1976 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. Min-Oo, G. & Lanier, L. L. Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection. J. Exp. Med. 211, 2669–2680 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nguyen, K. B. et al. Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection. J. Immunol. 169, 4279–4287 (2002).

    CAS  PubMed  Google Scholar 

  11. Sun, J. C. et al. Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J. Exp. Med. 209, 947–954 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ni, J., Miller, M., Stojanovic, A., Garbi, N. & Cerwenka, A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J. Exp. Med. 209, 2351–2365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Madera, S. & Sun, J. C. Cutting edge: stage-specific requirement of IL-18 for antiviral NK cell expansion. J. Immunol. 194, 1408–1412 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 10, e1004441 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Liu, L. L. et al. Critical role of CD2 co-stimulation in adaptive natural killer cell responses revealed in NKG2C-deficient humans. Cell Reports 15, 1088–1099 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ni, J. et al. Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4+ T cell help. OncoImmunology 5, e1219009 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018).In ref. 17, the authors show peptide-specific recognition of HCMV strains via the activating receptor NKG2C and how this affects the activation and population expansion and the epigenetic as well as transcriptional remodeling of NKG2C + NK cells.

    CAS  PubMed  Google Scholar 

  18. Beaulieu, A. M., Zawislak, C. L., Nakayama, T. & Sun, J. C. The transcription factor Zbtb32 controls the proliferative burst of virus-specific natural killer cells responding to infection. Nat. Immunol. 15, 546–553 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rapp, M. et al. Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses. Sci. Immunol. 2, eaan3796 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. Madera, S. et al. Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J. Exp. Med. 213, 225–233 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Costa-Garcia, M. et al. Antibody-mediated response of NKG2Cbright NK cells against human cytomegalovirus. J. Immunol. 194, 2715–2724 (2015).

    CAS  PubMed  Google Scholar 

  24. Bottino, C., Castriconi, R., Moretta, L. & Moretta, A. Cellular ligands of activating NK receptors. Trends Immunol. 26, 221–226 (2005).

    CAS  PubMed  Google Scholar 

  25. Diefenbach, A. & Raulet, D. H. Strategies for target cell recognition by natural killer cells. Immunol. Rev. 181, 170–184 (2001).

    CAS  PubMed  Google Scholar 

  26. Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lanier, L. L. Evolutionary struggles between NK cells and viruses. Nat. Rev. Immunol. 8, 259–268 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nabekura, T. et al. Cutting edge: NKG2D signaling enhances NK cell responses but alone is insufficient to drive expansion during mouse cytomegalovirus infection. J. Immunol. 199, 1567–1571 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Aoki, J. et al. Mouse homolog of poliovirus receptor-related gene 2 product, mPRR2, mediates homophilic cell aggregation. Exp. Cell Res. 235, 374–384 (1997).

    CAS  PubMed  Google Scholar 

  30. Reymond, N. et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J. Exp. Med. 199, 1331–1341 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nabekura, T. et al. Critical role of DNAX accessory molecule-1 (DNAM-1) in the development of acute graft-versus-host disease in mice. Proc. Natl. Acad. Sci. USA 107, 18593–18598 (2010).

    CAS  PubMed  Google Scholar 

  32. Ravens, I., Seth, S., Förster, R. & Bernhardt, G. Characterization and identification of Tage4 as the murine orthologue of human poliovirus receptor/CD155. Biochem. Biophys. Res. Commun. 312, 1364–1371 (2003).

    CAS  PubMed  Google Scholar 

  33. Soriani, A. et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511 (2009).

    CAS  PubMed  Google Scholar 

  34. Nabekura, T. et al. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40, 225–234 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rölle, A. et al. CD2-CD58 interactions are pivotal for the activation and function of adaptive natural killer cells in human cytomegalovirus infection. Eur. J. Immunol. 46, 2420–2425 (2016).

    PubMed  Google Scholar 

  36. Wang, E. C. Y. et al. Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses. Proc. Natl. Acad. Sci. USA 115, 4998–5003 (2018).

    CAS  PubMed  Google Scholar 

  37. Aguilar, O. A. et al. A viral immunoevasin controls innate immunity by targeting the prototypical natural killer cell receptor family. Cell 169, 58–71 (2017).

    CAS  PubMed  Google Scholar 

  38. Prichard, M. N., Penfold, M. E., Duke, G. M., Spaete, R. R. & Kemble, G. W. A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev. Med. Virol. 11, 191–200 (2001).

    CAS  PubMed  Google Scholar 

  39. Bukowski, J. F., Woda, B. A. & Welsh, R. M. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J. Virol. 52, 119–128 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Scalzo, A. A., Fitzgerald, N. A., Simmons, A., La Vista, A. B. & Shellam, G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).

    CAS  PubMed  Google Scholar 

  41. Scalzo, A. A. et al. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J. Immunol. 149, 581–589 (1992).

    CAS  PubMed  Google Scholar 

  42. Depatie, C., Muise, E., Lepage, P., Gros, P. & Vidal, S. M. High-resolution linkage map in the proximity of the host resistance locus Cmv1. Genomics 39, 154–163 (1997).

    CAS  PubMed  Google Scholar 

  43. Smith, K. M., Wu, J., Bakker, A. B., Phillips, J. H. & Lanier, L. L. Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161, 7–10 (1998).

    CAS  PubMed  Google Scholar 

  44. Bubić, I. et al. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J. Virol. 78, 7536–7544 (2004).

    PubMed  PubMed Central  Google Scholar 

  45. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    CAS  PubMed  Google Scholar 

  46. Smith, H. R. C. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99, 8826–8831 (2002). In refs. 45 and 46, the authors identify the MCMV protein m157 as the specific ligand for the NK cell activating receptor Ly49H and thereby for the first time describe a pathogen-specific recognition mechanism for NK cells.

    CAS  PubMed  Google Scholar 

  47. Dokun, A. O. et al. Specific and nonspecific NK cell activation during virus infection. Nat. Immunol. 2, 951–956 (2001).

    CAS  PubMed  Google Scholar 

  48. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).In ref. 48, the authors show the dramatic population-expansion potential of Ly49H + NK cells after transfer and infection and, notably, demonstrate superior protection by these cells during secondary infection, showing that NK cells can display memory properties in response to MCMV.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Schlub, T. E. et al. Comparing the kinetics of NK cells, CD4, and CD8 T cells in murine cytomegalovirus infection. J. Immunol. 187, 1385–1392 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Voigt, V. et al. Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells. Proc. Natl. Acad. Sci. USA 100, 13483–13488 (2003).

    CAS  PubMed  Google Scholar 

  51. French, A. R. et al. Escape of mutant double-stranded DNA virus from innate immune control. Immunity 20, 747–756 (2004).

    CAS  PubMed  Google Scholar 

  52. Berry, R. et al. Targeting of a natural killer cell receptor family by a viral immunoevasin. Nat. Immunol. 14, 699–705 (2013).

    CAS  PubMed  Google Scholar 

  53. Corbett, A. J., Coudert, J. D., Forbes, C. A. & Scalzo, A. A. Functional consequences of natural sequence variation of murine cytomegalovirus m157 for Ly49 receptor specificity and NK cell activation. J. Immunol. 186, 1713–1722 (2011).

    CAS  PubMed  Google Scholar 

  54. Pyzik, M. et al. Viral MHC class I-like molecule allows evasion of NK cell effector responses in vivo. J. Immunol. 193, 6061–6069 (2014).

    CAS  PubMed  Google Scholar 

  55. Desrosiers, M.-P. et al. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nat. Genet. 37, 593–599 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Pyzik, M. et al. Distinct MHC class I-dependent NK cell-activating receptors control cytomegalovirus infection in different mouse strains. J. Exp. Med. 208, 1105–1117 (2011). In ref. 56, additional receptors of the Ly49 family are reported to specifically recognize MCMV via the viral ligand m04 in mouse strains other than C57BL/6, highlighting the general importance of this recognition mode of NK cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kielczewska, A. et al. Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response. J. Exp. Med. 206, 515–523 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Babić, M. et al. Cytomegalovirus immunoevasin reveals the physiological role of ‘missing self’ recognition in natural killer cell dependent virus control in vivo. J. Exp. Med. 207, 2663–2673 (2010).

    PubMed  PubMed Central  Google Scholar 

  59. Gumá, M. et al. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104, 3664–3671 (2004).In ref. 59, the authors report for the first time dominant imprinting of HCMV on the NK cell population and note the striking population expansion of NKG2C + NK cells, setting the stage for further studies of this population in humans.

    PubMed  Google Scholar 

  60. Kuijpers, T. W. et al. Human NK cells can control CMV infection in the absence of T cells. Blood 112, 914–915 (2008).

    CAS  PubMed  Google Scholar 

  61. 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).

    PubMed  Google Scholar 

  62. Foley, B. et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119, 2665–2674 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Foley, B. et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C+ NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J. Immunol. 189, 5082–5088 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Béziat, V. et al. CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur. J. Immunol. 42, 447–457 (2012).

    PubMed  Google Scholar 

  65. Béziat, V. et al. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121, 2678–2688 (2013).

    PubMed  PubMed Central  Google Scholar 

  66. Della Chiesa, M. et al. Human cytomegalovirus infection promotes rapid maturation of NK cells expressing activating killer Ig-like receptor in patients transplanted with NKG2C-/- umbilical cord blood. J. Immunol. 192, 1471–1479 (2014).

    PubMed  Google Scholar 

  67. Lanier, L. L., Corliss, B., Wu, J. & Phillips, J. H. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693–701 (1998).

    CAS  PubMed  Google Scholar 

  68. Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    CAS  PubMed  Google Scholar 

  69. Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl. Acad. Sci. USA 95, 5199–5204 (1998).

    CAS  PubMed  Google Scholar 

  70. Brooks, A. G. et al. Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J. Immunol. 162, 305–313 (1999). The studies in refs. 68–70 describe HLA-E as the ligand for receptors of the NKG2 family and how the presentation of leader peptides on HLA-E allows NK cells to surveil the expression of classical HLA class I.

    CAS  PubMed  Google Scholar 

  71. Gumá, M. et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107, 3624–3631 (2006).

    PubMed  Google Scholar 

  72. Rölle, A. et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).

    CAS  PubMed  Google Scholar 

  74. Michaëlsson, J. et al. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J. Exp. Med. 196, 1403–1414 (2002).

    PubMed  PubMed Central  Google Scholar 

  75. Llano, M. et al. HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors: preferential response to an HLA-G-derived nonamer. Eur. J. Immunol. 28, 2854–2863 (1998).

    CAS  PubMed  Google Scholar 

  76. Valés-Gómez, M., Reyburn, H. T., Erskine, R. A., López-Botet, M. & Strominger, J. L. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J. 18, 4250–4260 (1999).

    PubMed  PubMed Central  Google Scholar 

  77. Cerboni, C. et al. Synergistic effect of IFN-γ and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity. Eur. J. Immunol. 31, 2926–2935 (2001).

    CAS  PubMed  Google Scholar 

  78. Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000).

    CAS  PubMed  Google Scholar 

  79. Ulbrecht, M. et al. Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis.J. Immunol. 164, 5019–5022 (2000). In refs. 78,79, the authors demonstrate how the HCMV protein gpUL40 can substitute for leader peptides derived from HLA class I to upregulate HLA-E and thereby protect HCMV against lysis by NKG2A + NK cells.

    CAS  PubMed  Google Scholar 

  80. Wang, E. C. Y. et al. UL40-mediated NK evasion during productive infection with human cytomegalovirus. Proc. Natl. Acad. Sci. USA 99, 7570–7575 (2002).

    CAS  PubMed  Google Scholar 

  81. Garrigue, I. et al. Variability of UL18, UL40, UL111a and US3 immunomodulatory genes among human cytomegalovirus clinical isolates from renal transplant recipients. J. Clin. Virol. 40, 120–128 (2007).

    CAS  PubMed  Google Scholar 

  82. Garrigue, I. et al. UL40 human cytomegalovirus variability evolution patterns over time in renal transplant recipients. Transplantation 86, 826–835 (2008).

    CAS  PubMed  Google Scholar 

  83. Heatley, S. L. et al. Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. J. Biol. Chem. 288, 8679–8690 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Noyola, D. E. et al. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children. Eur. J. Immunol. 42, 3256–3266 (2012).

    CAS  PubMed  Google Scholar 

  85. van der Ploeg, K. et al. Modulation of human leukocyte antigen-c by human cytomegalovirus stimulates KIR2DS1 recognition by natural killer cells. Front. Immunol. 8, 298 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. Chapel, A. et al. Peptide-specific engagement of the activating NK cell receptor KIR2DS1. Sci. Rep. 7, 2414 (2017).

    PubMed  PubMed Central  Google Scholar 

  87. Björkström, N. K., Svensson, A., Malmberg, K.-J., Eriksson, K. & Ljunggren, H.-G. Characterization of natural killer cell phenotype and function during recurrent human HSV-2 infection. PLoS One 6, e27664 (2011).

    PubMed  PubMed Central  Google Scholar 

  88. Lünemann, A., Vanoaica, L. D., Azzi, T., Nadal, D. & Münz, C. A distinct subpopulation of human NK cells restricts B cell transformation by EBV. J. Immunol. 191, 4989–4995 (2013).

    PubMed  Google Scholar 

  89. Azzi, T. et al. Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124, 2533–2543 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Jost, S. & Altfeld, M. Control of human viral infections by natural killer cells. Annu. Rev. Immunol. 31, 163–194 (2013).

    CAS  PubMed  Google Scholar 

  91. Neufeldt, C. J., Cortese, M., Acosta, E. G. & Bartenschlager, R. Rewiring cellular networks by members of the Flaviviridae family. Nat. Rev. Microbiol. 16, 125–142 (2018).

    CAS  PubMed  Google Scholar 

  92. Naiyer, M. M. et al. KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C. Sci. Immunol. 2, eaal5296 (2017).In ref. 92, the authors report a peptide from the HCV viralhelicase NS3 that is conserved among flaviviruses and specifically binds to KIR2DS2 and elicitsresponses by KIR2DS2 NK cells to HCV-infected cells.

    PubMed  Google Scholar 

  93. Kolykhalov, A. A., Mihalik, K., Feinstone, S. M. & Rice, C. M. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J. Virol. 74, 2046–2051 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ahlenstiel, G. et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology 138, 325–35.e1–2 (2010).

    CAS  PubMed  Google Scholar 

  95. Malone, D. F. G. et al. Cytomegalovirus-driven adaptive-like natural killer cell expansions are unaffected by concurrent chronic hepatitis virus infections. Front. Immunol. 8, 525 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. Petitdemange, C. et al. Longitudinal analysis of natural killer cells in dengue virus-infected patients in comparison to chikungunya and chikungunya/dengue virus-infected patients. PLoS Negl. Trop. Dis. 10, e0004499 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. Lunemann, S. et al. Sequence variations in HCV core-derived epitopes alter binding of KIR2DL3 to HLA-C*03:04 and modulate NK cell function. J. Hepatol. 65, 252–258 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Winter, C. C., Gumperz, J. E., Parham, P., Long, E. O. & Wagtmann, N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J. Immunol. 161, 571–577 (1998).

    CAS  PubMed  Google Scholar 

  99. Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).

    CAS  PubMed  Google Scholar 

  100. Knapp, S. et al. Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 51, 1168–1175 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kottilil, S. et al. Innate immunity in human immunodeficiency virus infection: effect of viremia on natural killer cell function. J. Infect. Dis. 187, 1038–1045 (2003).

    PubMed  Google Scholar 

  102. 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).

    CAS  PubMed  Google Scholar 

  103. Martin, M. P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31, 429–434 (2002).

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Alter, G. et al. HLA class I subtype-dependent expansion of KIR3DS1+ and KIR3DL1+ NK cells during acute human immunodeficiency virus type 1 infection. J. Virol. 83, 6798–6805 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gillespie, G. M. A. et al. Lack of KIR3DS1 binding to MHC class I Bw4 tetramers in complex with CD8+ T cell epitopes. AIDS Res. Hum. Retroviruses 23, 451–455 (2007).

    CAS  PubMed  Google Scholar 

  107. O’Connor, G. M. et al. Peptide-dependent recognition of HLA-B*57:01 by KIR3DS1. J. Virol. 89, 5213–5221 (2015).

    PubMed  PubMed Central  Google Scholar 

  108. O’Connor, G. M. et al. Analysis of binding of KIR3DS1*014 to HLA suggests distinct evolutionary history of KIR3DS1. J. Immunol. 187, 2162–2171 (2011).

    PubMed  PubMed Central  Google Scholar 

  109. Garcia-Beltran, W. F. et al. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat. Immunol. 17, 1067–1074 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Alter, G. et al. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476, 96–100 (2011). In ref. 110, the authors elucidate the basis for a genetic correlation of KIR2DL2 with HIV polymorphisms by demonstrating differential inhibition of KIR2DL2+ NK cells by peptides encoded by these polymorphic regions of the HIV genome.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Fadda, L. et al. HLA-Cw*0102-restricted HIV-1p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function. PLoS Pathog. 8, e1002805 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. van Teijlingen, N. H. et al. Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA-C*03:04 and modulate primary natural killer cell function. AIDS 28, 1399–1408 (2014).

    PubMed  Google Scholar 

  113. Hölzemer, A. et al. Selection of an HLA-C*03:04-restricted HIV-1 p24 Gag sequence variant is associated with viral escape from KIR2DL3+ natural killer cells: data from an observational cohort in South Africa. PLoS Med. 12, e1001900 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Ma, M. et al. NKG2C+NKG2A– natural killer cells are associated with a lower viral set point and may predict disease progression in individuals with primary HIV infection. Front. Immunol. 8, 1176 (2017).

    PubMed  PubMed Central  Google Scholar 

  115. Gondois-Rey, F. et al. NKG2C+ memory-like NK cells contribute to the control of HIV viremia during primary infection: Optiprim-ANRS 147. Clin. Transl. Immunology 6, e150 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Björkström, N. K. et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J. Exp. Med. 208, 13–21 (2011).

    PubMed  PubMed Central  Google Scholar 

  118. Petitdemange, C. et al. Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog. 7, e1002268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Gumá, M. et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J. Infect. Dis. 194, 38–41 (2006).

    PubMed  Google Scholar 

  120. Brunetta, E. et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS 24, 27–34 (2010).

    PubMed  Google Scholar 

  121. Davis, Z. B. et al. A conserved HIV-1-derived peptide presented by HLA-E renders infected T-cells highly susceptible to attack by NKG2A/CD94-bearing natural killer cells. PLoS Pathog. 12, e1005421 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. Reeves, R. K. et al. Antigen-specific NK cell memory in rhesus macaques. Nat. Immunol. 16, 927–932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Biassoni, R. et al. Molecular and functional characterization of NKG2D, NKp80, and NKG2C triggering NK cell receptors in rhesus and cynomolgus macaques: monitoring of NK cell function during simian HIV infection. J. Immunol. 174, 5695–5705 (2005).

    CAS  PubMed  Google Scholar 

  124. Walter, L. & Petersen, B. Diversification of both KIR and NKG2 natural killer cell receptor genes in macaques — implications for highly complex MHC-dependent regulation of natural killer cells. Immunology 150, 139–145 (2017).

    CAS  PubMed  Google Scholar 

  125. Lemmermann, N. A. W. et al. Immune evasion proteins of murine cytomegalovirus preferentially affect cell surface display of recently generated peptide presentation complexes. J. Virol. 84, 1221–1236 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by the Leibniz ScienceCampus Chronic Inflammation, the German Research Foundation (SFB-TRR241, RO3565/2-1 and RO3565/4-1 to C.R.), the German Research Foundation Heisenberg Program (RO 3565/1-1 for C.R.) and the Leibniz Graduate School for Rheumatology (Q.H.).

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  1. Quirin Hammer

    Present address: Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

  2. These authors contributed equally: Quirin Hammer, Timo Rückert.

Authors and Affiliations

  1. Innate Immunity, German Rheumatism Research Center, Leibniz Association, Berlin, Germany

    Quirin Hammer, Timo Rückert & Chiara Romagnani

  2. Medical Department I, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Chiara Romagnani

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Hammer, Q., Rückert, T. & Romagnani, C. Natural killer cell specificity for viral infections. Nat Immunol 19, 800–808 (2018). https://doi.org/10.1038/s41590-018-0163-6

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