#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection


Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection.


Vyšlo v časopise: Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection. PLoS Pathog 8(9): e32767. doi:10.1371/journal.ppat.1002915
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002915

Souhrn

Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection.


Zdroje

1. ColonnaM, KrugA, CellaM (2002) Interferon-producing cells: on the front line in immune responses against pathogens. Curr Opin Immunol 14: 373–379.

2. Asselin-PaturelC, BoonstraA, DalodM, DurandI, YessaadN, et al. (2001) Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2: 1144–1150.

3. BjorckP (2001) Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood 98: 3520–3526.

4. NakanoH, YanagitaM, GunnMD (2001) CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med 194: 1171–1178.

5. SwieckiM, ColonnaM (2010) Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev 234: 142–162.

6. CisseB, CatonML, LehnerM, MaedaT, ScheuS, et al. (2008) Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135: 37–48.

7. SwieckiM, GilfillanS, VermiW, WangY, ColonnaM (2010) Plasmacytoid dendritic cell ablation impacts early interferon responses and antiviral NK and CD8(+) T cell accrual. Immunity 33: 955–966.

8. TakagiH, FukayaT, EizumiK, SatoY, SatoK, et al. (2011) Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity invivo. Immunity 35: 958–971.

9. BlasiusAL, ArnoldCN, GeorgelP, RutschmannS, XiaY, et al. (2010) Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 107: 19973–19978.

10. SasawatariS, OkamuraT, KasumiE, Tanaka-FuruyamaK, Yanobu-TakanashiR, et al. (2011) The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterology 140: 1513–1525.

11. KhanolkarA, FullerMJ, ZajacAJ (2002) T cell responses to viral infections: lessons from lymphocytic choriomeningitis virus. Immunol Res 26: 309–321.

12. KimPS, AhmedR (2010) Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 22: 223–230.

13. ZunigaEI, McGavernDB, Pruneda-PazJL, TengC, OldstoneMB (2004) Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection. Nat Immunol 5: 1227–1234.

14. TortiN, WaltonSM, MurphyKM, OxeniusA (2011) Batf3 transcription factor-dependent DC subsets in murine CMV infection: differential impact on T-cell priming and memory inflation. Eur J Immunol 41: 2612–2618.

15. SchoenbergerSP, van der VoortEI, KrietemeijerGM, OffringaR, MeliefCJ, et al. (1998) Cross-priming of CTL responses in vivo does not require antigenic peptides in the endoplasmic reticulum of immunizing cells. J Immunol 161: 3808–3812.

16. HogquistKA, JamesonSC, HeathWR, HowardJL, BevanMJ, et al. (1994) T cell receptor antagonist peptides induce positive selection. Cell 76: 17–27.

17. CernyA, HueginAW, SutterS, BazinH, HengartnerHH, et al. (1986) Immunity to lymphocytic choriomeningitis virus in B cell-depleted mice: evidence for B cell and antibody-independent protection by memory T cells. Eur J Immunol 16: 913–917.

18. WelshRM, DundonPL, EynonEE, BrubakerJO, KooGC, et al. (1990) Demonstration of the antiviral role of natural killer cells in vivo with a natural killer cell-specific monoclonal antibody (NK 1.1). Nat Immun Cell Growth Regul 9: 112–120.

19. AicheleP, UnsoeldH, KoschellaM, SchweierO, KalinkeU, et al. (2006) CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion. J Immunol (Baltimore, Md : 1950) 176: 4525–4529.

20. Havenar-DaughtonC, KolumamGA, Murali-KrishnaK (2006) Cutting Edge: The direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J Immunol (Baltimore, Md : 1950) 176: 3315–3319.

21. KolumamGA, ThomasS, ThompsonLJ, SprentJ, Murali-KrishnaK (2005) Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med 202: 637–650.

22. ThompsonLJ, KolumamGA, ThomasS, Murali-KrishnaK (2006) Innate inflammatory signals induced by various pathogens differentially dictate the IFN-I dependence of CD8 T cells for clonal expansion and memory formation. J Immunol (Baltimore, Md : 1950) 177: 1746–1754.

23. WieselM, KratkyW, OxeniusA (2011) Type I IFN substitutes for T cell help during viral infections. J Immunol (Baltimore, Md : 1950) 186: 754–763.

24. ConrySJ, MilkovichKA, YonkersNL, RodriguezB, BernsteinHB, et al. (2009) Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function. J Virol 83: 11175–11187.

25. DrobitsB, HolcmannM, AmbergN, SwieckiM, GrundtnerR, et al. (2012) Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 122: 575–585.

26. Cervantes-BarraganL, LewisKL, FirnerS, ThielV, HuguesS, et al. (2012) Plasmacytoid dendritic cells control T-cell response to chronic viral infection. Proc Natl Acad Sci U S A 109: 3012–3017.

27. BocharovG, LudewigB, BertolettiA, KlenermanP, JuntT, et al. (2004) Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses. J Virol 78: 2247–2254.

28. WangY, SwieckiM, CellaM, AlberG, SchreiberRD, et al. (2012) Timing and Magnitude of Type I Interferon Responses by Distinct Sensors Impact CD8 T Cell Exhaustion and Chronic Viral Infection. Cell Host Microbe 11: 631–642.

29. OuR, ZhouS, HuangL, MoskophidisD (2001) Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J Virol 75: 8407–8423.

30. MatloubianM, ConcepcionRJ, AhmedR (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68: 8056–8063.

31. OldstoneMB, BlountP, SouthernPJ, LampertPW (1986) Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature 321: 239–243.

32. RietdijkST, BurwellT, BertinJ, CoyleAJ (2008) Sensing intracellular pathogens-NOD-like receptors. Curr Opin Pharmacol 8: 261–266.

33. WoltmanAM, Op den BrouwML, BiestaPJ, ShiCC, JanssenHL (2011) Hepatitis B virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function. PLoS One 6: e15324.

34. LiangH, RussellRS, YonkersNL, McDonaldD, RodriguezB, et al. (2009) Differential effects of hepatitis C virus JFH1 on human myeloid and plasmacytoid dendritic cells. J Virol 83: 5693–5707.

35. PopkinDL, TeijaroJR, SullivanBM, UrataS, RutschmannS, et al. (2011) Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner. Cell Host Microbe 9: 212–222.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2012 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#