Parasite Fate and Involvement of Infected Cells in the Induction of CD4 and CD8 T Cell Responses to
CD4+ and CD8+ T cells are critical for controlling many infections. To generate a T cell response during infection, T cells must encounter the microbial peptides that they recognize bound to MHC molecules on the surfaces of other cells, such as dendritic cells. It is currently unclear how dendritic cells acquire the antigens they present to T cells during infection with many intracellular pathogens. It is possible that these antigens are phagocytosed and processed by dendritic cells, or antigens may be presented by cells that are infected by pathogens such as Toxoplasma gondii, which invades host cells independently of phagocytosis. To differentiate these pathways, we developed a novel technique to track the fate of T. gondii in vivo that distinguishes actively infected cells from those that phagocytosed parasites. This technique was used to examine each of these cell populations. We also used pharmacological inhibitors of parasite invasion, and the transfer of sort-purified infected or uninfected dendritic cells and macrophages to determine what roles phagocytosis and active invasion have in the initiation of T cell responses. Our results demonstrate that phagocytosis of parasites is not sufficient to induce CD4+ or CD8+ T cell responses, whereas infected cells are critical for this process.
Vyšlo v časopise:
Parasite Fate and Involvement of Infected Cells in the Induction of CD4 and CD8 T Cell Responses to. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004047
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004047
Souhrn
CD4+ and CD8+ T cells are critical for controlling many infections. To generate a T cell response during infection, T cells must encounter the microbial peptides that they recognize bound to MHC molecules on the surfaces of other cells, such as dendritic cells. It is currently unclear how dendritic cells acquire the antigens they present to T cells during infection with many intracellular pathogens. It is possible that these antigens are phagocytosed and processed by dendritic cells, or antigens may be presented by cells that are infected by pathogens such as Toxoplasma gondii, which invades host cells independently of phagocytosis. To differentiate these pathways, we developed a novel technique to track the fate of T. gondii in vivo that distinguishes actively infected cells from those that phagocytosed parasites. This technique was used to examine each of these cell populations. We also used pharmacological inhibitors of parasite invasion, and the transfer of sort-purified infected or uninfected dendritic cells and macrophages to determine what roles phagocytosis and active invasion have in the initiation of T cell responses. Our results demonstrate that phagocytosis of parasites is not sufficient to induce CD4+ or CD8+ T cell responses, whereas infected cells are critical for this process.
Zdroje
1. DubeyJP (2008) The history of Toxoplasma gondii–the first 100 years. The Journal of eukaryotic microbiology 55: 467–475.
2. WeissLM, DubeyJP (2009) Toxoplasmosis: A history of clinical observations. International journal for parasitology 39: 895–901.
3. GazzinelliRT, WysockaM, HayashiS, DenkersEY, HienyS, et al. (1994) Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 153: 2533–2543.
4. SuzukiY, OrellanaMA, SchreiberRD, RemingtonJS (1988) Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 240: 516–518.
5. GazzinelliR, XuY, HienyS, CheeverA, SherA (1992) Simultaneous depletion of CD4+ and CD8+ T lymphocytes is required to reactivate chronic infection with Toxoplasma gondii. Journal of immunology 149: 175–180.
6. GoldszmidRS, SherA (2010) Processing and presentation of antigens derived from intracellular protozoan parasites. Current opinion in immunology 22: 118–123.
7. DupontCD, ChristianDA, HunterCA (2012) Immune response and immunopathology during toxoplasmosis. Seminars in immunopathology 34: 793–813.
8. BrodeS, MacaryPA (2004) Cross-presentation: dendritic cells and macrophages bite off more than they can chew!. Immunology 112: 345–351.
9. SteinmanRM, HawigerD, NussenzweigMC (2003) Tolerogenic dendritic cells. Annual review of immunology 21: 685–711.
10. JohnB, HarrisTH, TaitED, WilsonEH, GreggB, et al. (2009) Dynamic Imaging of CD8(+) T cells and dendritic cells during infection with Toxoplasma gondii. PLoS Pathog 5: e1000505.
11. ChtanovaT, HanSJ, SchaefferM, van DoorenGG, HerzmarkP, et al. (2009) Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node. Immunity 31: 342–355.
12. GoldszmidRS, CoppensI, LevA, CasparP, MellmanI, et al. (2009) Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J Exp Med 206: 399–410.
13. DzierszinskiF, PepperM, StumhoferJS, LaRosaDF, WilsonEH, et al. (2007) Presentation of Toxoplasma gondii antigens via the endogenous major histocompatibility complex class I pathway in nonprofessional and professional antigen-presenting cells. Infect Immun 75: 5200–5209.
14. GubbelsMJ, StriepenB, ShastriN, TurkozM, RobeyEA (2005) Class I major histocompatibility complex presentation of antigens that escape from the parasitophorous vacuole of Toxoplasma gondii. Infection and immunity 73: 703–711.
15. DenkersEY, YapG, Scharton-KerstenT, CharestH, ButcherBA, et al. (1997) Perforin-mediated cytolysis plays a limited role in host resistance to Toxoplasma gondii. Journal of immunology 159: 1903–1908.
16. LuderCG, LangT, BeuerleB, GrossU (1998) Down-regulation of MHC class II molecules and inability to up-regulate class I molecules in murine macrophages after infection with Toxoplasma gondii. Clinical and experimental immunology 112: 308–316.
17. LuderCG, WalterW, BeuerleB, MaeurerMJ, GrossU (2001) Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1alpha. European journal of immunology 31: 1475–1484.
18. McKeeAS, DzierszinskiF, BoesM, RoosDS, PearceEJ (2004) Functional inactivation of immature dendritic cells by the intracellular parasite Toxoplasma gondii. J Immunol 173: 2632–2640.
19. NeefjesJ, JongsmaML, PaulP, BakkeO (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nature reviews Immunology 11: 823–836.
20. DongreAR, KovatsS, deRoosP, McCormackAL, NakagawaT, et al. (2001) In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. European journal of immunology 31: 1485–1494.
21. NuchternJG, BiddisonWE, KlausnerRD (1990) Class II MHC molecules can use the endogenous pathway of antigen presentation. Nature 343: 74–76.
22. MalnatiMS, MartiM, LaVauteT, JaraquemadaD, BiddisonW, et al. (1992) Processing pathways for presentation of cytosolic antigen to MHC class II-restricted T cells. Nature 357: 702–704.
23. PaludanC, SchmidD, LandthalerM, VockerodtM, KubeD, et al. (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307: 593–596.
24. NimmerjahnF, MilosevicS, BehrendsU, JaffeeEM, PardollDM, et al. (2003) Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. European journal of immunology 33: 1250–1259.
25. BonifazLC, ArzateS, MorenoJ (1999) Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. European journal of immunology 29: 119–131.
26. AichingerG, KarlssonL, JacksonMR, VestbergM, VaughanJH, et al. (1997) Major histocompatibility complex class II-dependent unfolding, transport, and degradation of endogenous proteins. The Journal of biological chemistry 272: 29127–29136.
27. JaraquemadaD, MartiM, LongEO (1990) An endogenous processing pathway in vaccinia virus-infected cells for presentation of cytoplasmic antigens to class II-restricted T cells. The Journal of experimental medicine 172: 947–954.
28. WeissS, BogenB (1991) MHC class II-restricted presentation of intracellular antigen. Cell 64: 767–776.
29. LichJD, ElliottJF, BlumJS (2000) Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. The Journal of experimental medicine 191: 1513–1524.
30. IwasakiA, MedzhitovR (2010) Regulation of adaptive immunity by the innate immune system. Science 327: 291–295.
31. FoxBA, BzikDJ (2002) De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Nature 415: 926–929.
32. WilsonDC, MatthewsS, YapGS (2008) IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. J Immunol 180: 5935–5945.
33. WilsonDC, GrotenbregGM, LiuK, ZhaoY, FrickelEM, et al. (2010) Differential regulation of effector- and central-memory responses to Toxoplasma gondii Infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells. PLoS Pathog 6: e1000815.
34. SafferLD, Long KrugSA, SchwartzmanJD (1989) The role of phospholipase in host cell penetration by Toxoplasma gondii. The American journal of tropical medicine and hygiene 40: 145–149.
35. RavindranS, LodoenMB, VerhelstSH, BogyoM, BoothroydJC (2009) 4-Bromophenacyl bromide specifically inhibits rhoptry secretion during Toxoplasma invasion. PloS one 4: e8143.
36. MorgadoP, OngYC, BoothroydJC, LodoenMB (2011) Toxoplasma gondii induces B7-2 expression through activation of JNK signal transduction. Infection and immunity 79: 4401–4412.
37. ChikteS, PanchalN, WarnesG (2013) Use of LysoTracker dyes: A flow cytometric study of autophagy. Cytometry Part A : the journal of the International Society for Analytical Cytology 85(2): 169–78.
38. JordanKA, WilsonEH, TaitED, FoxBA, RoosDS, et al. (2009) Kinetics and phenotype of vaccine-induced CD8+ T-cell responses to Toxoplasma gondii. Infection and immunity 77: 3894–3901.
39. HowardJC, HunnJP, SteinfeldtT (2011) The IRG protein-based resistance mechanism in mice and its relation to virulence in Toxoplasma gondii. Current opinion in microbiology 14: 414–421.
40. LingYM, ShawMH, AyalaC, CoppensI, TaylorGA, et al. (2006) Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. The Journal of experimental medicine 203: 2063–2071.
41. MartensS, ParvanovaI, ZerrahnJ, GriffithsG, SchellG, et al. (2005) Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases. PLoS pathogens 1: e24.
42. GigleyJP, FoxBA, BzikDJ (2009) Cell-mediated immunity to Toxoplasma gondii develops primarily by local Th1 host immune responses in the absence of parasite replication. J Immunol 182: 1069–1078.
43. ParraD, RiegerAM, LiJ, ZhangYA, RandallLM, et al. (2012) Pivotal advance: peritoneal cavity B-1 B cells have phagocytic and microbicidal capacities and present phagocytosed antigen to CD4+ T cells. Journal of leukocyte biology 91: 525–536.
44. GoldszmidRS, CasparP, RivollierA, WhiteS, DzutsevA, et al. (2012) NK cell-derived interferon-gamma orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection. Immunity 36: 1047–1059.
45. JungS, UnutmazD, WongP, SanoG, De los SantosK, et al. (2002) In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17: 211–220.
46. PepperM, PaganAJ, IgyartoBZ, TaylorJJ, JenkinsMK (2011) Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35: 583–595.
47. GroverHS, BlanchardN, GonzalezF, ChanS, RobeyEA, et al. (2012) The Toxoplasma gondii peptide AS15 elicits CD4 T cells that can control parasite burden. Infection and immunity 80: 3279–3288.
48. RaiD, PhamNL, HartyJT, BadovinacVP (2009) Tracking the total CD8 T cell response to infection reveals substantial discordance in magnitude and kinetics between inbred and outbred hosts. Journal of immunology 183: 7672–7681.
49. McDermottDS, VargaSM (2011) Quantifying antigen-specific CD4 T cells during a viral infection: CD4 T cell responses are larger than we think. Journal of immunology 187: 5568–5576.
50. ScholzenT, GerdesJ (2000) The Ki-67 protein: from the known and the unknown. Journal of cellular physiology 182: 311–322.
51. McKennaHJ, StockingKL, MillerRE, BraselK, De SmedtT, et al. (2000) Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95: 3489–3497.
52. HildnerK, EdelsonBT, PurthaWE, DiamondM, MatsushitaH, et al. (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322: 1097–1100.
53. DunayIR, FuchsA, SibleyLD (2010) Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun 78: 1564–1570.
54. SavinaA, JancicC, HuguesS, GuermonprezP, VargasP, et al. (2006) NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126: 205–218.
55. SubausteCS, WessendarpM (2000) Human dendritic cells discriminate between viable and killed Toxoplasma gondii tachyzoites: dendritic cell activation after infection with viable parasites results in CD28 and CD40 ligand signaling that controls IL-12-dependent and -independent T cell production of IFN-gamma. Journal of immunology 165: 1498–1505.
56. SeiderK, HeykenA, LuttichA, MiramonP, HubeB (2010) Interaction of pathogenic yeasts with phagocytes: survival, persistence and escape. Current opinion in microbiology 13: 392–400.
57. ShinS, RoyCR (2008) Host cell processes that influence the intracellular survival of Legionella pneumophila. Cellular microbiology 10: 1209–1220.
58. RohdeK, YatesRM, PurdyGE, RussellDG (2007) Mycobacterium tuberculosis and the environment within the phagosome. Immunological reviews 219: 37–54.
59. da SilvaCV, CruzL, Araujo NdaS, AngeloniMB, FonsecaBB, et al. (2012) A glance at Listeria and Salmonella cell invasion: different strategies to promote host actin polymerization. International journal of medical microbiology : IJMM 302: 19–32.
60. DunnJD, ValdiviaRH (2010) Uncivil engineers: Chlamydia, Salmonella and Shigella alter cytoskeleton architecture to invade epithelial cells. Future microbiology 5: 1219–1232.
61. RomanoPS, CuetoJA, CasassaAF, VanrellMC, GottliebRA, et al. (2012) Molecular and cellular mechanisms involved in the Trypanosoma cruzi/host cell interplay. IUBMB life 64: 387–396.
62. OverstreetMG, CockburnIA, ChenYC, ZavalaF (2008) Protective CD8 T cells against Plasmodium liver stages: immunobiology of an ‘unnatural’ immune response. Immunological reviews 225: 272–283.
63. LangC, AlgnerM, BeinertN, GrossU, LuderCG (2006) Diverse mechanisms employed by Toxoplasma gondii to inhibit IFN-gamma-induced major histocompatibility complex class II gene expression. Microbes and infection/Institut Pasteur 8: 1994–2005.
64. WalsengE, FurutaK, GoldszmidRS, WeihKA, SherA, et al. (2010) Dendritic cell activation prevents MHC class II ubiquitination and promotes MHC class II survival regardless of the activation stimulus. The Journal of biological chemistry 285: 41749–41754.
65. SubausteCS, de Waal MalefytR, FuhF (1998) Role of CD80 (B7.1) and CD86 (B7.2) in the immune response to an intracellular pathogen. Journal of immunology 160: 1831–1840.
66. BairdJR, FoxBA, SandersKL, LizottePH, Cubillos-RuizJR, et al. (2013) Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment. Cancer research 73: 3842–3851.
67. Mourao-SaD, RoyS, BlanderJM (2013) Vita-PAMPs: signatures of microbial viability. Advances in experimental medicine and biology 785: 1–8.
68. LambertH, HitzigerN, DellacasaI, SvenssonM, BarraganA (2006) Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination. Cellular microbiology 8: 1611–1623.
69. WeidnerJM, BarraganA (2013) Tightly regulated migratory subversion of immune cells promotes the dissemination of Toxoplasma gondii. International journal for parasitology 44(2): 85–90.
70. FuksJM, ArrighiRB, WeidnerJM, Kumar MenduS, JinZ, et al. (2012) GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS pathogens 8: e1003051.
71. WeidnerJM, KanataniS, Hernandez-CastanedaMA, FuksJM, RethiB, et al. (2013) Rapid cytoskeleton remodelling in dendritic cells following invasion by Toxoplasma gondii coincides with the onset of a hypermigratory phenotype. Cellular microbiology 15: 1735–1752.
72. LambertH, Dellacasa-LindbergI, BarraganA (2011) Migratory responses of leukocytes infected with Toxoplasma gondii. Microbes and infection/Institut Pasteur 13: 96–102.
73. ZhaoYO, KhaminetsA, HunnJP, HowardJC (2009) Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS pathogens 5: e1000288.
74. ZhaoZ, FuxB, GoodwinM, DunayIR, StrongD, et al. (2008) Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell host & microbe 4: 458–469.
75. RomaoS, GannageM, MunzC (2013) Checking the garbage bin for problems in the house, or how autophagy assists in antigen presentation to the immune system. Seminars in cancer biology 23(5): 391–6.
76. KoshyAA, FoutsAE, LodoenMB, AlkanO, BlauHM, et al. (2010) Toxoplasma secreting Cre recombinase for analysis of host-parasite interactions. Nature methods 7: 307–309.
77. KoshyAA, DietrichHK, ChristianDA, MelehaniJH, ShastriAJ, et al. (2012) Toxoplasma co-opts host cells it does not invade. PLoS pathogens 8: e1002825.
78. GigleyJP, FoxBA, BzikDJ (2009) Long-term immunity to lethal acute or chronic type II Toxoplasma gondii infection is effectively induced in genetically susceptible C57BL/6 mice by immunization with an attenuated type I vaccine strain. Infect Immun 77: 5380–5388.
79. van HeijstJWJ, GerlachC, SwartE, SieD, Nunes-AlvesC, et al. (2009) Recruitment of Antigen-Specific CD8(+) T Cells in Response to Infection Is Markedly Efficient. Science 325: 1265–1269.
80. DreschC, LeverrierY, MarvelJ, ShortmanK (2012) Development of antigen cross-presentation capacity in dendritic cells. Trends in immunology 33: 381–388.
81. CurtsingerJM, MescherMF (2010) Inflammatory cytokines as a third signal for T cell activation. Current Opinion in Immunology 22: 333–340.
82. MoonJJ, HuangB, IrvineDJ (2012) Engineering nano- and microparticles to tune immunity. Advanced materials 24: 3724–3746.
83. WhitmarshRJ, GrayCM, GreggB, ChristianDA, MayMJ, et al. (2011) A critical role for SOCS3 in innate resistance to Toxoplasma gondii. Cell Host Microbe 10: 224–236.
84. PepperM, DzierszinskiF, CrawfordA, HunterCA, RoosD (2004) Development of a system to study CD4+-T-cell responses to transgenic ovalbumin-expressing Toxoplasma gondii during toxoplasmosis. Infect Immun 72: 7240–7246.
85. MessinaM, NiesmanI, MercierC, SibleyLD (1995) Stable DNA transformation of Toxoplasma gondii using phleomycin selection. Gene 165: 213–217.
86. HaqueA, GrailleM, KasperLH, HaqueS (1999) Immunization with heat-killed Toxoplasma gondii stimulates an early IFN-gamma response and induces protection against virulent murine malaria. Vaccine 17: 2604–2611.
87. RobbenPM, MordueDG, TruscottSM, TakedaK, AkiraS, et al. (2004) Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype. Journal of immunology 172: 3686–3694.
88. BlasiE, RadziochD, MerlettiL, VaresioL (1989) Generation of macrophage cell line from fresh bone marrow cells with a myc/raf recombinant retrovirus. Cancer biochemistry biophysics 10: 303–317.
89. CurranMA, AllisonJP (2009) Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer research 69: 7747–7755.
90. MaraskovskyE, PulendranB, BraselK, TeepeM, RouxER, et al. (1997) Dramatic numerical increase of functionally mature dendritic cells in FLT3 ligand-treated mice. Advances in experimental medicine and biology 417: 33–40.
91. FentressSJ, BehnkeMS, DunayIR, MashayekhiM, RommereimLM, et al. (2010) Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell host & microbe 8: 484–495.
92. HenrySC, DaniellXG, BurroughsAR, IndaramM, HowellDN, et al. (2009) Balance of Irgm protein activities determines IFN-gamma-induced host defense. Journal of leukocyte biology 85: 877–885.
93. McIlvaineT (1921) A buffer solution for colorimetric comparaison. J Biol Chem 49: 183–186.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2014 Číslo 4
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- The 2010 Cholera Outbreak in Haiti: How Science Solved a Controversy
- Coxsackievirus-Induced miR-21 Disrupts Cardiomyocyte Interactions via the Downregulation of Intercalated Disk Components
- An Overview of Respiratory Syncytial Virus
- , , , Genetic Variability: Cryptic Biological Species or Clonal Near-Clades?