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Functional interactions between dendritic cells and NK cells during viral infection

Nature Immunology volume 4, pages 175–181 (2003)Cite this article

Abstract

Ly49H+NK1.1+ natural killer (NK) cells are essential for the control of murine cytomegalovirus (MCMV) during the acute stage of infection. This cell subset expands at the later stages of infection in an MCMV-specific fashion. Here we demonstrate a critical interaction between Ly49H+ NK cells and CD8α+ dendritic cells (DCs) whereby the presence of Ly49H+ NK cells results in maintenance of CD8α+ DCs in the spleen during acute MCMV infection. Reciprocally, CD8α+ DCs are essential for the expansion of Ly49H+ NK cells by a mechanism involving interleukin 18 (IL-18) and IL-12. This study provides evidence for a functional interrelationship between DCs and NK cells during viral infection and defines some of the critical cytokines.

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Figure 1: MCMV replication and splenic DC phenotype after infection of resistant (B6) and susceptible (BALB/c) mice.
Figure 2: The presence of NK cells is required to retain CD8α+ DCs in the spleen during MCMV infection.
Figure 3: The fate of splenic CD8α+ DCs after MCMV infection is linked to loci within the NKC.
Figure 4: Ly49H-mediated effects are critical for the maintenance of CD8α+ DCs in the spleen after MCMV infection.
Figure 5: CD8α+ DCs are required for the expansion of Ly49H+, NK1.1+ NK cells that occurs following MCMV infection.
Figure 6: The cross-talk between CD8α+ DCs and Ly49H+ NK cells does not involve the IPC DC subset.
Figure 7: IL-12 and IL-18 are required for the expansion of Ly49H+, NK1.1+ NK cells after MCMV infection.

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References

  1. Alford, C.A. & Britt, W.J. Cytomegalovirus. in Virology (ed. Fields, B.N.) 629–660 (Raven Press, New York, 1996).

    Google Scholar 

  2. Messerle, M., Keil, G.M., Schneider, K. & Koszinowski, U.H. Characterization of the murine cytomegalovirus genes encoding the major DNA binding protein and the ICP18.5 homolog. Virology 191, 355–367 (1992).

    Article  CAS  Google Scholar 

  3. Naniche, D. & Oldstone, M.B.A. Generalized immunosuppression: How viruses undermine the immune response. Cell. Mol. Life. Sci. 57, 1399–1407 (1999).

    Article  Google Scholar 

  4. Andrews, D.M., Andoniou, C.E., Granucci, F., Ricciardi-Castagnoli, P. & Degli-Esposti, M.A. Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nat. Immunol. 2, 1077–1084 (2001).

    Article  CAS  Google Scholar 

  5. Raftery, M.J. et al. Targeting the function of mature dendritic cells by human cytomegalovirus: A multilayered viral defense strategy. Immunity 15, 997–1009 (2001).

    Article  CAS  Google Scholar 

  6. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  Google Scholar 

  7. Vremec, D., Pooley, J., Hochrein, H., Wu, L. & Shortman, K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164, 2978–2986 (2000).

    Article  CAS  Google Scholar 

  8. Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2, 1144–1150 (2001).

    Article  CAS  Google Scholar 

  9. Bjorck, P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood 98, 3520–3526 (2001).

    Article  CAS  Google Scholar 

  10. Nakano, H., Yanagita, M. & Gunn, M.D. CD11c+B220+Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med. 194, 1171–1178 (2001).

    Article  CAS  Google Scholar 

  11. Martin, P. et al. Dramatic increase in lymph node dendritic cell number during infection by the mouse mammary tumor virus occurs by a CD62L-dependent blood-borne DC recruitment. Blood 99, 1282–1288 (2002).

    Article  CAS  Google Scholar 

  12. del Hoyo, G.M., Martin, P., Arias, C.F., Marin, A.R. & Ardavin, C. CD8α+ dendritic cells originate from the CD8α− dendritic cell subset by a maturation process involving CD8α, DEC-205, and CD24 up-regulation. Blood 99, 999–1004 (2002).

    Article  Google Scholar 

  13. Grumont, R. et al. c-Rel regulates interleukin 12 p70 expression in CD8+ dendritic cells by specifically inducing p35 gene transcription. J. Exp. Med. 194, 1021–1032 (2001).

    Article  CAS  Google Scholar 

  14. Hochrein, H. et al. Differential production of IL-12, IFN-α, and IFN-γ by mouse dendritic cell subsets. J. Immunol. 166, 5448–5455 (2001).

    Article  CAS  Google Scholar 

  15. den Haan, J.M.M., Lehar, S.M. & Bevan, M.J. CD8+ but not CD8− dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192, 1685–1695 (2001).

    Article  Google Scholar 

  16. Fernandez, N.C. et al. Dendritic cells directly trigger NK cell functions: Cross-talk relevant in innate anti-tumor immune responses in vivo. Nat. Med. 5, 405–411 (1999).

    Article  CAS  Google Scholar 

  17. Reichlin, A. & Yokoyama, W.M. Natural killer cell proliferation induced by anti-NK1.1 and IL-2. Immunol. Cell Biol. 76, 143–152 (1998).

    Article  CAS  Google Scholar 

  18. Orange, J.S. & Biron, C.A. Characterization of early IL-12, IFN-α/β, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J. Immunol. 156, 4746–4756 (1996).

    CAS  PubMed  Google Scholar 

  19. Orange, J.S. & Biron, C.A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-γ production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J. Immunol. 156, 1138–1142 (1996).

    CAS  PubMed  Google Scholar 

  20. Hochrein, H. et al. Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J. Exp. Med. 192, 823–1032 (2000).

    Article  CAS  Google Scholar 

  21. Trinchieri, G. Interleukin-12 and interferon-γ. Do they always go together? Am. J. Pathol. 147, 1534–1538 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gerosa, F. et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327–333 (2002).

    Article  CAS  Google Scholar 

  23. Ferlazzo, G. et al. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J. Exp. Med. 195, 343–333 (2002).

    Article  CAS  Google Scholar 

  24. Piccioli, D., Sbrana, S., Melandri, E. & Valiante, N.M. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J. Exp. Med. 195, 335–333 (2002).

    Article  CAS  Google Scholar 

  25. 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 

  26. Bancroft, G.J., Shellam, G.R. & Chalmer, J.E. Genetic influences on the augmentation of natural killer (NK) cells during murine cytomegalovirus infection: Correlation with patterns of resistance. J. Immunol. 126, 988–994 (1981).

    CAS  PubMed  Google Scholar 

  27. Shellam, G.R., Allan, J.E., Papadimitriou, J.M. & Bancroft, G.J. Increased susceptibility to cytomegalovirus infection in beige mutant mice. Proc. Natl. Acad. Sci. USA 78, 5104–5108 (1981).

    Article  CAS  Google Scholar 

  28. Scalzo, A.A., Fitzgerald, N.A., Simmons, A., La Vista, A.B. & Shellam, G.R. Cmv1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).

    Article  CAS  Google Scholar 

  29. Forbes, C.A. et al. The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6. Genomics 41, 406–413 (1997).

    Article  CAS  Google Scholar 

  30. Daniels, K.A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).

    Article  CAS  Google Scholar 

  31. Brown, M.G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    Article  CAS  Google Scholar 

  32. Lee, S.H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Natural Genet. 28, 42–45 (2001).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Welsh, R.M., O'Donnell, C.L. & Shultz, L.D. Antiviral activity of NK 1.1+ natural killer cells in C57BL/6 scid mice infected with murine cytomegalovirus. Nat. Immunity 13, 239–245 (1994).

    CAS  Google Scholar 

  35. Scalzo, A.A. et al. The effect of the Cmv1 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 

  36. Scalzo, A.A. et al. Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci. Immunogenetics 49, 238–241 (1999).

    Article  CAS  Google Scholar 

  37. Smyth, M.J. et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755–844 (2000).

    Article  CAS  Google Scholar 

  38. Dokun, A.O., Chu, D.T., Yang, L.P., Bendelac, A.S. & Yokoyama, W.M. Analysis of in situ NK cell responses during viral infection. J. Immunol. 167, 5286–5293 (2001).

    Article  CAS  Google Scholar 

  39. Talmadge, J.E., Meyers, K.M., Prieur, D.J. & Starkey, J.R. Role of NK cells in tumour growth and metastasis in beige mice. Nature 284, 622–624 (1980).

    Article  CAS  Google Scholar 

  40. Biron, C.A. & Brossay, L. NK cells and NKT cells in innate defense against viral infections. Curr. Opin. Immunol. 13, 458–464 (2001).

    Article  CAS  Google Scholar 

  41. Lathbury, L.J., Allan, J.E., Shellam, G.R. & Scalzo, A.A. Effect of host genotype in determining the relative roles of natural killer cells and T cells in mediating protection against murine cytomegalovirus infection. J. Gen. Virol. 77, 2605–2613 (1996).

    Article  CAS  Google Scholar 

  42. Su, H.C. et al. NK cell functions restrain T cell responses during viral infections. Eur. J. Immunol. 31, 3048–3055 (2001).

    Article  CAS  Google Scholar 

  43. Orange, J.S. & Biron, C.A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-γ production and antiviral defence—studies of natural killer and T cell responses in contrasting viral infections. J. Immunol. 156, 1138–1142 (1138).

    Google Scholar 

  44. Pien, G.C., Satoskar, A.R., Takeda, K., Akira, S. & Biron, C.A. Selective IL-18 requirements for induction of compartmental IFN-γ responses during viral infection. J. Immunol. 165, 4787–4791 (2000).

    Article  CAS  Google Scholar 

  45. Stober, D., Schirmbeck, R. & Reimann, J. IL-12/IL-18-dependent IFN-γ release by murine dendritic cells. J. Immunol. 167, 957–965 (2001).

    Article  CAS  Google Scholar 

  46. Vremec, D. et al. The surface phenotype of dendritic cells purified from mouse thymus and spleen: Investigation of the CD8 expression by a subpopulation of dendritic cells. J. Exp. Med. 176, 47–58 (1992).

    Article  CAS  Google Scholar 

  47. Martin, P. et al. Concept of lymphoid versus myeloid dendritic cell lineages revisited: both CD8α− and CD8α+ dendritic cells are generated from CD4low lymphoid-committed precursors. Blood 96, 2511–2519 (2000).

    CAS  PubMed  Google Scholar 

  48. Allan, J.E. & Shellam, G.R. Genetic control of murine cytomegalovirus infection: virus titres in resistant and susceptible strains of mice. Arch. Virol. 81, 139–150 (1984).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Wikstrom of The Lotteries Commission of Western Australia Flow Cytometry and Cell Sorting Facility for assistance, and G. Shellam and D. Godfrey for critical reading of this manuscript. Supported by the National Health and Medical Research Council of Australia, a Wellcome Trust Overseas Senior Research Fellowship in Biomedical Science in Australia (M.A.D.-E.) and an AMRAD Pharmaceuticals Scholarship (D.M.A.).

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Authors and Affiliations

  1. Department of Microbiology, School of Biomedical and Chemical Sciences, The University of Western Australia, Nedlands, Perth, Western Australia, Australia

    Daniel M. Andrews, Anthony A. Scalzo & Mariapia A. Degli-Esposti

  2. Rheumatology Division, Departments of Medicine, Pathology and Immunology, Washington University School of Medicine, St. Louis, MI, USA

    Wayne M. Yokoyama

  3. Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia

    Mark J. Smyth

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Correspondence to Mariapia A. Degli-Esposti.

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Andrews, D., Scalzo, A., Yokoyama, W. et al. Functional interactions between dendritic cells and NK cells during viral infection. Nat Immunol 4, 175–181 (2003). https://doi.org/10.1038/ni880

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