Direct TLR2 Signaling Is Critical for NK Cell Activation and Function in Response to Vaccinia Viral Infection
Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections.
Vyšlo v časopise:
Direct TLR2 Signaling Is Critical for NK Cell Activation and Function in Response to Vaccinia Viral Infection. PLoS Pathog 6(3): e32767. doi:10.1371/journal.ppat.1000811
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000811
Souhrn
Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections.
Zdroje
1. MossB
2007 Poxviridae: the viruses and their replication.
KnipeDM
HowleyPM
Fields Virology, 5th ed Philadelphia Lippincott Williams & Wilkins 2905 2945
2. FennerF
HendersonD
AritaI
JezekZ
LadnyiI
1988 Small-pox and Its Eradication Geneva World Health Organization 1460
3. HendersonDA
1999 The looming threat of bioterrorism. Science 283 1279 1282
4. LaneHC
MontagneJL
FauciAS
2001 Bioterrorism: a clear and present danger. Nat Med 7 1271 1273
5. CohenJ
2001 Bioterrorism. Smallpox vaccinations: how much protection remains? Science 294 985
6. BaxbyD
1991 Safety of recombinant vaccinia vaccines. Lancet 337 913
7. BrayM
WrightME
2003 Progressive vaccinia. Clin Infect Dis 36 766 774
8. BoossJ
DavisLE
2003 Smallpox and smallpox vaccination: neurological implications. Neurology 60 1241 1245
9. LaneJM
GoldsteinJ
2003 Adverse events occurring after smallpox vaccination. Semin Pediatr Infect Dis 14 189 195
10. FrenchAR
YokoyamaWM
2003 Natural killer cells and viral infections. Curr Opin Immunol 15 45 51
11. LeeSH
MiyagiT
BironCA
2007 Keeping NK cells in highly regulated antiviral warfare. Trends Immunol 28 252 259
12. BironCA
ByronKS
SullivanJL
1989 Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320 1731 1735
13. BukowskiJF
WodaBA
HabuS
OkumuraK
WelshRM
1983 Natural killer cell depletion enhances virus synthesis and virus-induced hepatitis in vivo. J Immunol 131 1531 1538
14. NatukRJ
WelshRM
1987 Accumulation and chemotaxis of natural killer/large granular lymphocytes at sites of virus replication. J Immunol 138 877 883
15. ParkerAK
ParkerS
YokoyamaWM
CorbettJA
BullerRM
2007 Induction of natural killer cell responses by ectromelia virus controls infection. J Virol 81 4070 4079
16. MartinezJ
HuangX
YangY
2008 Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. J Immunol 180 1592 1597
17. LanierLL
2008 Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9 495 502
18. BrownMG
DokunAO
HeuselJW
SmithHR
BeckmanDL
2001 Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292 934 937
19. AraseH
MocarskiES
CampbellAE
HillAB
LanierLL
2002 Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296 1323 1326
20. MandelboimO
LiebermanN
LevM
PaulL
ArnonTI
2001 Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409 1055 1060
21. GazitR
GrudaR
ElboimM
ArnonTI
KatzG
2006 Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol 7 517 523
22. GumaM
AnguloA
Lopez-BotetM
2006 NK cell receptors involved in the response to human cytomegalovirus infection. Curr Top Microbiol Immunol 298 207 223
23. AndoniouCE
van DommelenSL
VoigtV
AndrewsDM
BrizardG
2005 Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat Immunol 6 1011 1019
24. DokunAO
KimS
SmithHR
KangHS
ChuDT
2001 Specific and nonspecific NK cell activation during virus infection. Nat Immunol 2 951 956
25. DanielsKA
DevoraG
LaiWC
O'DonnellCL
BennettM
2001 Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J Exp Med 194 29 44
26. ChisholmSE
ReyburnHT
2006 Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors. J Virol 80 2225 2233
27. FangM
LanierLL
SigalLJ
2008 A role for NKG2D in NK cell-mediated resistance to poxvirus disease. PLoS Pathog 4 e30 doi:10.1371/journal.ppat.0040030
28. ZhuJ
MartinezJ
HuangX
YangY
2007 Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-{beta}. Blood 109 619 625
29. SivoriS
FalcoM
Della ChiesaM
CarlomagnoS
VitaleM
2004 CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci U S A 101 10116 10121
30. SchmidtKN
LeungB
KwongM
ZaremberKA
SatyalS
2004 APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J Immunol 172 138 143
31. HartOM
Athie-MoralesV
O'ConnorGM
GardinerCM
2005 TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 175 1636 1642
32. GelmanAE
LaRosaDF
ZhangJ
WalshPT
ChoiY
2006 The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity 25 783 793
33. JiangK
ZhongB
GilvaryDL
CorlissBC
Hong-GellerE
2000 Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nat Immunol 1 419 425
34. TassiI
CellaM
GilfillanS
TurnbullI
DiacovoTG
2007 p110gamma and p110delta phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity 27 214 227
35. QuigleyM
MartinezJ
HuangX
YangY
2009 A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Blood 113 2256 2264
36. Kurt-JonesEA
PopovaL
KwinnL
HaynesLM
JonesLP
2000 Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1 398 401
37. BiebackK
LienE
KlaggeIM
AvotaE
Schneider-SchauliesJ
2002 Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 76 8729 8736
38. RassaJC
MeyersJL
ZhangY
KudaravalliR
RossSR
2002 Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci U S A 99 2281 2286
39. KarupiahG
CouparBE
AndrewME
BoyleDB
PhillipsSM
1990 Elevated natural killer cell responses in mice infected with recombinant vaccinia virus encoding murine IL-2. J Immunol 144 290 298
40. Martin-FontechaA
ThomsenLL
BrettS
GerardC
LippM
2004 Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5 1260 1265
41. ArnonTI
AchdoutH
LiebermanN
GazitR
Gonen-GrossT
2004 The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46. Blood 103 664 672
42. YangY
HuangCT
HuangX
PardollDM
2004 Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5 508 515
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 3
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Binds and Protects a Nuclear Noncoding RNA from Cellular RNA Decay Pathways
- Endocytosis of the Anthrax Toxin Is Mediated by Clathrin, Actin and Unconventional Adaptors
- Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8 T Cells
- Inhibition of Macrophage Migration Inhibitory Factor Ameliorates Ocular -Induced Keratitis