Skip to main content

Advertisement

SpringerLink
Log in

Caspase-8 restricts natural killer cell accumulation during MCMV Infection

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Natural killer (NK) cells provide important host defense against herpesvirus infections and influence subsequent T cell control of replication and maintenance of latency. NK cells exhibit phases of expansion, contraction and memory formation in response to the natural mouse pathogen murine cytomegalovirus (MCMV). Innate and adaptive immune responses are tightly regulated in mammals to avoid excess tissue damage while preventing acute and chronic viral disease and assuring resistance to reinfection. Caspase (CASP)8 is an autoactivating aspartate-specific cysteine protease that initiates extrinsic apoptosis and prevents receptor interacting protein (RIP) kinase (RIPK)1–RIPK3-driven necroptosis. CASP8 also promotes death-independent signal transduction. All of these activities make contributions to inflammation. Here, we demonstrate that CASP8 restricts NK cell expansion during MCMV infection but does not influence NK memory. Casp8−/−Ripk3−/− mice mount higher NK response levels than Casp8+/−Ripk3−/− littermate controls or WT C57BL/6 J mice, indicating that RIPK3 deficiency alone does not contribute to NK response patterns. MCMV m157-responsive Ly49H+ NK cells support increased expansion of both Ly49H− NK cells and CD8 T cells in Casp8−/−Ripk3−/− mice. Surprisingly, hyperaccumulation of NK cells depends on the pronecrotic kinase RIPK1. Ripk1−/−Casp8−/−Ripk3−/− mice fail to show the enhanced expansion of lymphocytes observed in Casp8−/−Ripk3−/− mice even though development and homeostasis are preserved in uninfected Ripk1−/−Casp8−/−Ripk3−/− mice. Thus, CASP8 naturally regulates the magnitude of NK cell responses in response to infection where strong activation signals depend on another key regulator of death signaling, RIPK1. In addition, the strong NK cell response promotes survival of effector CD8 T cells during their expansion. Thus, hyperaccumulation of NK cells and crosstalk with T cells becomes amplified in the absence of extrinsic cell death machinery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sun JC, Lanier LL (2011) NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol 11:645–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV, Iizuka K, Furukawa H, Beckman DL, Pingel JT, Scalzo AA, Fremont DH, Yokoyama WM (2002) Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 99:8826–8831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Picarda G, Benedict CA (2018) Cytomegalovirus: shape-shifting the immune system. J Immunol 200:3881–3889

    Article  CAS  PubMed  Google Scholar 

  5. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457:557–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, Lopez-Botet M (2004) Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104:3664–3671

    Article  CAS  PubMed  Google Scholar 

  8. Guma M, Cabrera C, Erkizia I, Bofill M, Clotet B, Ruiz L, Lopez-Botet M (2006) 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

    Article  PubMed  Google Scholar 

  9. Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, Lanier LL (2011) Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci USA 108:14725–14732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lam VC, Lanier LL (2017) NK cells in host responses to viral infections. Curr Opin Immunol 44:43–51

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Geary CD, Krishna C, Lau CM, Adams NM, Gearty SV, Pritykin Y, Thomsen AR, Leslie CS, Sun JC (2018) Non-redundant ISGF3 components promote NK cell survival in an auto-regulatory manner during viral infection. Cell Rep 24(1949–1957):e1946

    Google Scholar 

  13. Adams NM, Lau CM, Fan X, Rapp M, Geary CD, Weizman OE, Diaz-Salazar C, Sun JC (2018) Transcription factor IRF8 orchestrates the adaptive natural killer cell response. Immunity 48(1172–1182):e1176

    Google Scholar 

  14. Madera S, Rapp M, Firth MA, Beilke JN, Lanier LL, Sun JC (2016) Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J Exp Med 213:225–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Orange JS, Biron CA (1996) An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol 156:1138–1142

    CAS  PubMed  Google Scholar 

  16. Nguyen KB, Salazar-Mather TP, Dalod MY, Van Deusen JB, Wei XQ, Liew FY, Caligiuri MA, Durbin JE, Biron CA (2002) Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 169:4279–4287

    Article  CAS  PubMed  Google Scholar 

  17. Nabekura T, Gotthardt D, Niizuma K, Trsan T, Jenus T, Jonjic S, Lanier LL (2017) Cutting Edge: NKG2D signaling enhances NK cell responses but alone is insufficient to drive expansion during mouse cytomegalovirus infection. J Immunol 199:1567–1571

    Article  CAS  PubMed  Google Scholar 

  18. Kurtulus S, Tripathi P, Hildeman DA (2012) Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development. Front Immunol 3:404

    PubMed  Google Scholar 

  19. Bouillet P, O’Reilly LA (2009) CD95, BIM and T cell homeostasis. Nat Rev Immunol 9:514–519

    Article  CAS  PubMed  Google Scholar 

  20. Min-Oo G, Bezman NA, Madera S, Sun JC, Lanier LL (2014) Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J Exp Med 211:1289–1296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Min-Oo G, Kamimura Y, Hendricks DW, Nabekura T, Lanier LL (2013) NK cells: walking three paths down memory lane. Trends Immunol 34:251–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mocarski ES, Guo H, Kaiser WJ (2015) Necroptosis: the Trojan horse in cell autonomous antiviral host defense. Virology 479–480:160–166

    Article  PubMed  CAS  Google Scholar 

  23. Mocarski ES, Kaiser WJ, Livingston-Rosanoff D, Upton JW, Daley-Bauer LP (2014) True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity. J Immunol 192:2019–2026

    Article  CAS  PubMed  Google Scholar 

  24. Mocarski ES, Upton JW, Kaiser WJ (2012) Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nat Rev Immunol 12:79–88

    Article  CAS  Google Scholar 

  25. Tummers B, Green DR (2017) Caspase-8: regulating life and death. Immunol Rev 277:76–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Masson F, Kupresanin F, Mount A, Strasser A, Belz GT (2011) Bid and Bim collaborate during induction of T cell death in persistent infection. J Immunol 186:4059–4066

    Article  CAS  PubMed  Google Scholar 

  27. Feng Y, Livingston-Rosanoff D, Roback L, Sundararajan A, Speck SH, Mocarski ES, Daley-Bauer LP (2018) Remarkably robust antiviral immune response despite combined deficiency in caspase-8 and RIPK3. J Immunol 201:2244–2255

    Article  CAS  PubMed  Google Scholar 

  28. Feng Y, Daley-Bauer LP, Roback L, Guo H, Koehler HS, Potempa M, Lanier LL, Mocarski ES (2019) Caspase-8 restricts antiviral CD8 T cell hyperaccumulation. Proc Natl Acad Sci USA (In press)

  29. Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419:395–399

    Article  CAS  PubMed  Google Scholar 

  30. Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J, Salmena L, Hakem R, Straus S, Lenardo M (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307:1465–1468

    Article  CAS  PubMed  Google Scholar 

  31. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB, Huang C, Sundararajan A, Guo H, Roback L, Speck SH, Bertin J, Gough PJ, Balachandran S, Mocarski ES (2014) RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci USA 111:7753–7758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, Lich JD, Finger J, Kasparcova V, Votta B, Ouellette M, King BW, Wisnoski D, Lakdawala AS, DeMartino MP, Casillas LN, Haile PA, Sehon CA, Marquis RW, Upton J, Daley-Bauer LP, Roback L, Ramia N, Dovey CM, Carette JE, Chan FK, Bertin J, Gough PJ, Mocarski ES, Kaiser WJ (2014) RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell 56:481–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dokun AO, Kim S, Smith HR, Kang HS, Chu DT, Yokoyama WM (2001) Specific and nonspecific NK cell activation during virus infection. Nat Immunol 2:951–956

    Article  CAS  PubMed  Google Scholar 

  35. Robbins SH, Bessou G, Cornillon A, Zucchini N, Rupp B, Ruzsics Z, Sacher T, Tomasello E, Vivier E, Koszinowski UH, Dalod M (2007) Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog 3:e123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mitrovic M, Arapovic J, Jordan S, Fodil-Cornu N, Ebert S, Vidal SM, Krmpotic A, Reddehase MJ, Jonjic S (2012) The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response. J Virol 86:2165–2175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Andrews DM, Scalzo AA, Yokoyama WM, Smyth MJ, Degli-Esposti MA (2003) Functional interactions between dendritic cells and NK cells during viral infection. Nat Immunol 4:175–181

    Article  CAS  PubMed  Google Scholar 

  38. Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, Scalzo AA, Smyth MJ, Degli-Esposti MA (2010) Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 207:1333–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lau CM, Sun JC (2018) The widening spectrum of immunological memory. Curr Opin Immunol 54:42–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kurtulus S, Sholl A, Toe J, Tripathi P, Raynor J, Li KP, Pellegrini M, Hildeman DA (2015) Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins. Cell Death Differ 22:174–184

    Article  CAS  PubMed  Google Scholar 

  41. Arechiga AF, Bell BD, Leverrier S, Weist BM, Porter M, Wu Z, Kanno Y, Ramos SJ, Ong ST, Siegel R, Walsh CM (2007) A Fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2. J Immunol 179:5291–5300

    Article  CAS  PubMed  Google Scholar 

  42. Marcais A, Marotel M, Degouve S, Koenig A, Fauteux-Daniel S, Drouillard A, Schlums H, Viel S, Besson L, Allatif O, Blery M, Vivier E, Bryceson Y, Thaunat O, Walzer T (2017) High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors. Elife 6:e26423

    Article  PubMed  PubMed Central  Google Scholar 

  43. Marcais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, Rabilloud J, Mayol K, Tavares A, Bienvenu J, Gangloff YG, Gilson E, Vivier E, Walzer T (2014) The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 15:749–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ch’en IL, Beisner DR, Degterev A, Lynch C, Yuan J, Hoffmann A, Hedrick SM (2008) Antigen-mediated T cell expansion regulated by parallel pathways of death. Proc Natl Acad Sci USA 105:17463–17468

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hedrick SM, Ch’en IL, Alves BN (2010) Intertwined pathways of programmed cell death in immunity. Immunol Rev 236:41–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ch’en IL, Tsau JS, Molkentin JD, Komatsu M, Hedrick SM (2011) Mechanisms of necroptosis in T cells. J Exp Med 208:633–641

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Juilland M, Thome M (2018) Holding all the CARDs: how MALT1 controls CARMA/CARD-dependent signaling. Front Immunol 9:1927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Arechiga AF, Bell BD, Solomon JC, Chu IH, Dubois CL, Hall BE, George TC, Coder DM, Walsh CM (2005) Cutting edge: fADD is not required for antigen receptor-mediated NF-kappaB activation. J Immunol 175:7800–7804

    Article  CAS  PubMed  Google Scholar 

  49. Paulsen M, Janssen O (2011) Pro- and anti-apoptotic CD95 signaling in T cells. Cell Commun Signal 9:7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Sam Speck (Emory University) and Rafi Ahmed (Emory University) for reagents and discussion and Wolfram Brune (Heinrich Pette Institute) for ∆m157 MCMV. This research was supported the National Institute of Health (NIH) Tetramer Core Facility for MHC class I tetramers and the Emory Vaccine Center Flow Core for materials and Public Health Service Grants R01 AI020211 and AI118853 (to E.S.M.) as well as AI068129 (to L.L.L.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 1462 Clifton Rd. N.E, Atlanta, GA, 30322, USA

    Yanjun Feng, Lisa P. Daley-Bauer, Linda Roback & Edward S. Mocarski

  2. Department of Microbiology and Immunology and Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA, 94143, USA

    Marc Potempa & Lewis L. Lanier

Authors
  1. Yanjun Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa P. Daley-Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda Roback
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Potempa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lewis L. Lanier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward S. Mocarski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward S. Mocarski.

Ethics declarations

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval

Animal experiments were approved according to the United States Public Health Service National Institutes of Health and Emory University Institutional Animal Care and Use Committee guidelines.

Additional information

Edited by: Matthias J. Reddehase.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Special Issue on Immunological Imprinting during Chronic Viral Infection.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, Y., Daley-Bauer, L.P., Roback, L. et al. Caspase-8 restricts natural killer cell accumulation during MCMV Infection. Med Microbiol Immunol 208, 543–554 (2019). https://doi.org/10.1007/s00430-019-00617-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-019-00617-6

Keywords

Search

Navigation