The development of vaccines that can enhance immunity to viral pathogens is an important goal. However, the innate molecular pathways that regulate the strength and quality of the immune response remain largely uncharacterized. To define the role of Toll-like receptor (TLR) signaling in control of a model retroviral pathogen, Friend virus (FV), I generated mice in which the TLR signaling adapter Myd88 was selectively deleted in dendritic cell (DC) or in B cell lineages. Deletion of Myd88 in DCs had little effect on immune control of FV, while B cell specific deletion of Myd88 caused a dramatic increase in viral infectious centers and a significantly reduced antibody response, indicating that B cell-intrinsic TLR signaling plays a crucial role, while TLR signaling in DCs is less important. I then identified the single-stranded RNA sensing protein TLR7 as being required for antibody-mediated control of FV by analyzing mice deficient in TLR7. Remarkably, B cells in infected TLR7-deficient mice upregulated CD69 and CD86 early in infection, but failed to develop into germinal center B cells. CD4 T cell responses were also attenuated in the absence of TLR7, but CD8 responses were TLR7 independent, suggesting the existence of additional pathways for detection of retroviral particles. Together these results demonstrate that the vertebrate immune system detects retroviruses in vivo via TLR7 and that this pathway regulates a key checkpoint controlling development of germinal center B cells.
Vyšlo v časopise: Toll-like Receptor 7 Controls the Anti-Retroviral Germinal Center Response. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002293 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002293
1. BroderSGalloRC 1984 A pathogenic retrovirus (HTLV-III) linked to AIDS. N Engl J Med 311 1292 1297
2. Barre-SinoussiFChermannJCReyFNugeyreMTChamaretS 1983 Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220 868 871
3. PoieszBJRuscettiFWGazdarAFBunnPAMinnaJD 1980 Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 77 7415 7419
4. KimJHRerks-NgarmSExclerJLMichaelNL 2010 HIV vaccines: lessons learned and the way forward. Curr Opin HIV AIDS 5 428 434
5. KwongPDDoyleMLCasperDJCicalaCLeavittSA 2002 HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420 678 682
6. WeiXDeckerJMWangSHuiHKappesJC 2003 Antibody neutralization and escape by HIV-1. Nature 422 307 312
7. MikellISatherDNKalamsSAAltfeldMAlterG 2011 Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog 7 e1001251
8. PasareCMedzhitovR 2004 Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6 1382 1387
9. MedzhitovRLittmanD 2008 HIV immunology needs a new direction. Nature 455 591
10. IwasakiAMedzhitovR 2010 Regulation of adaptive immunity by the innate immune system. Science 327 291 295
11. ZhangJXDiehlGELittmanDR 2008 Relief of preintegration inhibition and characterization of additional blocks for HIV replication in primary mouse T cells. PLoS One 3 e2035
12. MyersLHasenkrugKJ 2009 Retroviral immunology: lessons from a mouse model. Immunol Res 43 160 166
13. MesserRJDittmerUPetersonKEHasenkrugKJ 2004 Essential role for virus-neutralizing antibodies in sterilizing immunity against Friend retrovirus infection. Proc Natl Acad Sci U S A 101 12260 12265
14. BrowneEPLittmanDR 2009 Myd88 is required for an antibody response to retroviral infection. PLoS Pathog 5 e1000298
15. RobertsonMNMiyazawaMMoriSCaugheyBEvansLH 1991 Production of monoclonal antibodies reactive with a denatured form of the Friend murine leukemia virus gp70 envelope protein: use in a focal infectivity assay, immunohistochemical studies, electron microscopy and western blotting. J Virol Methods 34 255 271
16. HornungVRothenfusserSBritschSKrugAJahrsdorferB 2002 Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168 4531 4537
17. HouBReizisBDeFrancoAL 2008 Toll-like receptors activate innate and adaptive immunity by using dendritic cell-intrinsic and -extrinsic mechanisms. Immunity 29 272 282
18. BartonGMMedzhitovR 2003 Toll-like receptor signaling pathways. Science 300 1524 1525
19. AdachiOKawaiTTakedaKMatsumotoMTsutsuiH 1998 Targeted disruption of the MyD88 gene results in loss of IL-1 - and IL-18-mediated function. Immunity 9 143 150
20. HemmiHTakeuchiOKawaiTKaishoTSatoS 2000 A Toll-like receptor recognizes bacterial DNA. Nature 408 740 745
21. HeilFHemmiHHochreinHAmpenbergerFKirschningC 2004 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303 1526 1529
22. KawaiTAdachiOOgawaTTakedaKAkiraS 1999 Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11 115 122
23. MeierAAlterGFrahmNSidhuHLiB 2007 MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81 8180 8191
24. McHeyzer-WilliamsLJPelletierNMarkLFazilleauNMcHeyzer-WilliamsMG 2009 Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol 21 266 273
25. BaloghAAdoriMTorokKMatkoJLaszloG 2010 A closer look into the GL7 antigen: its spatio-temporally selective differential expression and localization in lymphoid cells and organs in human. Immunol Lett 130 89 96
26. MuramatsuMSankaranandVSAnantSSugaiMKinoshitaK 1999 Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem 274 18470 18476
27. MuramatsuMKinoshitaKFagarasanSYamadaSShinkaiY 2000 Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102 553 563
28. AydarYSukumarSSzakalAKTewJG 2005 The influence of immune complex-bearing follicular dendritic cells on the IgM response, Ig class switching, and production of high affinity IgG. J Immunol 174 5358 5366
29. PasareCMedzhitovR 2005 Control of B-cell responses by Toll-like receptors. Nature 438 364 368
30. GavinALHoebeKDuongBOtaTMartinC 2006 Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314 1936 1938
31. Meyer-BahlburgAKhimSRawlingsDJ 2007 B cell intrinsic TLR signals amplify but are not required for humoral immunity. J Exp Med 204 3095 3101
32. HouBSaudanPOttGWheelerMLJiM 2011 Selective utilization of Toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity 34 375 384
33. KasturiSPSkountzouIAlbrechtRAKoutsonanosDHuaT 2011 Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470 543 547
34. BarrTABrownSMastroeniPGrayD 2009 B cell intrinsic MyD88 signals drive IFN-gamma production from T cells and control switching to IgG2c. J Immunol 183 1005 1012
35. BessaJKopfMBachmannMF 2010 Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner. J Immunol 184 4615 4619
36. KimHJWangXRadfarSSprouleTJRoopenianDC 2011 CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A 108 2010 2015
37. JegerlehnerAMaurerPBessaJHintonHJKopfM 2007 TLR9 signaling in B cells determines class switch recombination to IgG2a. J Immunol 178 2415 2420
38. GreenNMLawsAKieferKBusconiLKimYM 2009 Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. J Immunol 183 1569 1576
39. KimHJVerbinnenBTangXLuLCantorH 2010 Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467 328 332
40. PasareCMedzhitovR 2003 Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299 1033 1036
41. TakaokaAWangZChoiMKYanaiHNegishiH 2007 DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448 501 505
42. YoneyamaMKikuchiMNatsukawaTShinobuNImaizumiT 2004 The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5 730 737
43. ChiuYHMacmillanJBChenZJ 2009 RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138 576 591
44. ChoiMKWangZBanTYanaiHLuY 2009 A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proc Natl Acad Sci U S A 106 17870 17875
45. ManelNHogstadBWangYLevyDEUnutmazD 2010 A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467 214 217
46. OgawaTTsuji-KawaharaSYuasaTKinoshitaSChikaishiT 2011 Natural killer cells recognize friend retrovirus-infected erythroid progenitor cells through NKG2D-RAE-1 interactions In Vivo. J Virol 85 5423 5435
47. SantiagoMLMontanoMBenitezRMesserRJYonemotoW 2008 Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science 321 1343 1346
48. Tsuji-KawaharaSChikaishiTTakedaEKatoMKinoshitaS 2010 Persistence of viremia and production of neutralizing antibodies differentially regulated by polymorphic APOBEC3 and BAFF-R loci in friend virus-infected mice. J Virol 84 6082 6095
49. SantiagoMLBenitezRLMontanoMHasenkrugKJGreeneWC 2010 Innate retroviral restriction by Apobec3 promotes antibody affinity maturation in vivo. J Immunol 185 1114 1123
50. BlanchetFPMorisANikolicDSLehmannMCardinaudS 2010 Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 32 654 669
51. BaenzigerSHeikenwalderMJohansenPSchlaepferEHoferU 2009 Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood 113 377 388
52. KaneMCaseLKWangCYurkovetskiyLDikiyS 2011 Innate Immune Sensing of Retroviral Infection via Toll-like Receptor 7 Occurs upon Viral Entry. Immunity 35 135 145
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
