Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

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Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage.

Vyšlo v časopise: Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection. PLoS Pathog 7(11): e32767. doi:10.1371/journal.ppat.1002393
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002393

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1. ChakrabortySNazmiADuttaKBasuA 2010 Neurons under viral attack: victims or warriors? Neurochem Int 56 727 735

2. MelzerNMeuthSGWiendlH 2009 CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. Faseb J 23 3659 3673

3. GaleaIBechmannIPerryVH 2007 What is immune privilege (not)? Trends Immunol 28 12 18

4. GuidottiLGChisariFV 2001 Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19 65 91

5. BinderGKGriffinDE 2003 Immune-mediated clearance of virus from the central nervous system. Microbes Infect 5 439 448

6. DecmanVKinchingtonPRHarveySAHendricksRL 2005 Gamma interferon can block herpes simplex virus type 1 reactivation from latency, even in the presence of late gene expression. J Virol 79 10339 10347

7. KnickelbeinJEKhannaKMYeeMBBatyCJKinchingtonPR 2008 Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322 268 271

8. JolyEMuckeLOldstoneMB 1991 Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253 1283 1285

9. PattersonCEDaleyJKRallGF 2002 Neuronal survival strategies in the face of RNA viral infection. J Infect Dis 186 Suppl 2 S215 219

10. BoulangerLMShatzCJ 2004 Immune signalling in neural development, synaptic plasticity and disease. Nat Rev Neurosci 5 521 531

11. ShatzCJ 2009 MHC class I: an unexpected role in neuronal plasticity. Neuron 64 40 45

12. BienCGBauerJDeckwerthTLWiendlHDeckertM 2002 Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen's encephalitis. Ann Neurol 51 311 318

13. NeumannHCavalieAJenneDEWekerleH 1995 Induction of MHC class I genes in neurons. Science 269 549 552

14. MedanaIMartinicMAWekerleHNeumannH 2001 Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 159 809 815

15. MeuthSGHerrmannAMSimonOJSiffrinVMelzerN 2009 Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J Neurosci 29 15397 15409

16. de la TorreJC 1994 Molecular biology of borna disease virus: prototype of a new group of animal viruses. J Virol 68 7669 7675

17. SchneemannASchneiderPALambRALipkinWI 1995 The remarkable coding strategy of Borna disease virus: a new member of the nonsegmented negative strand RNA viruses. Virology 210 1 8

18. LudwigHBodeL 2000 Borna disease virus: new aspects on infection, disease, diagnosis and epidemiology. Rev Sci Tech 19 259 288

19. StaeheliPSauderCHausmannJEhrenspergerFSchwemmleM 2000 Epidemiology of Borna disease virus. J Gen Virol 81 2123 2135

20. PletnikovMGonzalez-DuniaDStitzL 2002 Experimental infection: pathogenesis of neurobehavioral disease. CarboneK Borna disease virus and its role in neurobehavioral disease Washington D.C. ASM press 125 178

21. Gonzalez-DuniaDVolmerRMayerDSchwemmleM 2005 Borna disease virus interference with neuronal plasticity. Virus Res 111 224 234

22. DeschlUStitzLHerzogSFreseKRottR 1990 Determination of immune cells and expression of major histocompatibility complex class II antigen in encephalitic lesions of experimental Borna disease. Acta Neuropathologica 81 41 50

23. StitzLBilzerTRichtJARottR 1993 Pathogenesis of Borna disease. Arch Virol [Suppl] 7 135 151

24. SobbeMBilzerTGommelSNöskeKPlanzO 1997 Induction of degenerative brain lesions after adoptive transfer of brain lymphocytes from Borna disease virus-infected rats: presence of CD8+ T cells and perforin mRNA. J Virol 71 2400 2407

25. StitzLBilzerTPlanzO 2002 The immunopathogenesis of Borna disease virus infection. Front Biosci 7 d541 555

26. PlanzOBilzerTSobbeMStitzL 1993 Lysis of major histocompatibility complex class I-bearing cells in Borna disease virus-induced degenerative encephalopathy. J Exp Med 178 163 174

27. MozhayevaMGSaraYLiuXKavalaliET 2002 Development of vesicle pools during maturation of hippocampal synapses. J Neurosci 22 654 665

28. PratCMSchmidSFarrugiaFCenacNLe MassonG 2009 Mutation of the protein kinase C site in borna disease virus phosphoprotein abrogates viral interference with neuronal signaling and restores normal synaptic activity. PLoS Pathog 5 e1000425

29. SuberbielleEStellaAPontFMonnetCMoutonE 2008 Proteomic analysis reveals selective impediment of neuronal remodeling upon Borna disease virus infection. J Virol 82 12265 12279

30. VolmerRPratCMLe MassonGGarenneAGonzalez-DuniaD 2007 Borna disease virus infection impairs synaptic plasticity. J Virol 81 8833 8837

31. BilzerTStitzL 1994 Immune-mediated brain atrophy. CD8+ T cells contribute to tissue destruction during Borna disease. J Immunol 1538 818 823

32. DuplanVSuberbielleENapperCEJolyESaoudiA 2007 Tracking antigen-specific CD8+ T cells in the rat using MHC class I multimers. J Immunol Methods 320 30 39

33. RobbinsPAMcMichaelAJ 1991 Immune recognition of HLA molecules downmodulates CD8 expression on cytotoxic T lymphocytes. J Exp Med 173 221 230

34. McDoleJRDanzerSCPunRYChenYJohnsonHL 2010 Rapid formation of extended processes and engagement of Theiler's virus-infected neurons by CNS-infiltrating CD8 T cells. Am J Pathol 177 1823 1833

35. BerdondiniLChiappaloneMvan der WalPDImfeldKde RooijNF 2006 A microelectrode array (MEA) integrated with clustering structures for investigating in vitro neurodynamics in confined interconnected sub-populations of neurons. Sens Actuators B Chem 114 530 541

36. NeumannHMedanaIMBauerJLassmannH 2002 Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 25 313 319

37. LassmannH 2010 Axonal and neuronal pathology in multiple sclerosis: what have we learnt from animal models. Exp Neurol 225 2 8

38. LiblauRSWongFSMarsLTSantamariaP 2002 Autoreactive CD8 T cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 17 1 6

39. CoscoyLGanemD 2000 Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci U S A 97 8051 8056

40. GuerinJLGelfiJBoullierSDelverdierMBellangerFA 2002 Myxoma virus leukemia-associated protein is responsible for major histocompatibility complex class I and Fas-CD95 down-regulation and defines scrapins, a new group of surface cellular receptor abductor proteins. J Virol 76 2912 2923

41. TortorellaDGewurzBEFurmanMHSchustDJPloeghHL 2000 Viral subversion of the immune system. Annu Rev Immunol 18 861 926

42. ShresthaBDiamondMS 2007 Fas ligand interactions contribute to CD8+ T-cell-mediated control of West Nile virus infection in the central nervous system. J Virol 81 11749 11757

43. ShresthaBSamuelMADiamondMS 2006 CD8+ T cells require perforin to clear West Nile virus from infected neurons. J Virol 80 119 129

44. DelhayeSPaulSBlakqoriGMinetMWeberF 2006 Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci U S A 103 7835 7840

45. Diaz-HernandezMHernandezFMartin-AparicioEGomez-RamosPMoranMA 2003 Neuronal induction of the immunoproteasome in Huntington's disease. J Neurosci 23 11653 11661

46. NeumannHSchmidtHCavalieAJenneDWekerleH 1997 Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med 185 305 316

47. TrandemKZhaoJFlemingEPerlmanS 2011 Highly activated cytotoxic CD8 T cells express protective IL-10 at the peak of coronavirus-induced encephalitis. J Immunol 186 3642 3652

48. ZhangNBevanMJ 2011 CD8(+) T cells: foot soldiers of the immune system. Immunity 35 161 168

49. SieversCPlattNPerryVHColemanMPConfortiL 2003 Neurites undergoing Wallerian degeneration show an apoptotic-like process with Annexin V positive staining and loss of mitochondrial membrane potential. Neurosci Res 46 161 169

50. RoedigerBArmatiPJ 2003 Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13 222 229

51. ZhangLDengTSunYLiuKYangY 2008 Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation. J Neurosci Res 86 2281 2291

52. KilincDGalloGBarbeeKA 2009 Mechanical membrane injury induces axonal beading through localized activation of calpain. Exp Neurol 219 553 561

53. ManningPTJohnsonEMJrWilcoxCLPalmatierMARussellJH 1987 MHC-specific cytotoxic T lymphocyte killing of dissociated sympathetic neuronal cultures. Am J Pathol 128 395 409

54. MedanaIMGallimoreAOxeniusAMartinicMMWekerleH 2000 MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol 30 3623 3633

55. Rensing-EhlAMalipieroUIrmlerMTschoppJConstamD 1996 Neurons induced to express major histocompatibility complex class I antigen are killed via the perforin and not the Fas (APO-1/CD95) pathway. Eur J Immunol 26 2271 2274

56. Chavez-GalanLArenas-Del AngelMCZentenoEChavezRLascurainR 2009 Cell death mechanisms induced by cytotoxic lymphocytes. Cell Mol Immunol 6 15 25

57. KagiDLedermannBBurkiKZinkernagelRMHengartnerH 1996 Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Annu Rev Immunol 14 207 232

58. PoenischMBurgerNStaeheliPBauerGSchneiderU 2009 Protein X of Borna disease virus inhibits apoptosis and promotes viral persistence in the central nervous systems of newborn-infected rats. J Virol 83 4297 4307

59. NikicIMerklerDSorbaraCBrinkoetterMKreutzfeldtM 2011 A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17 495 499

60. BajramovicJJMünterSSyanSNerhbassUBrahicM 2003 Borna disease virus glycoprotein is required for viral dissemination in neurons. J Virol 77 12222 12231

61. HansABajramovicJJSyanSPerretEDuniaI 2004 Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. Faseb J 18 863 865

62. IraniDNGriffinDE 1991 Isolation of brain parenchymal lymphocytes for flow cytometric analysis. Application to acute viral encephalitis. J Immunol Methods 139 223 231

63. BernardIFoucrasGCautainBvan der MeidePHDruetP 1998 Flow cytometric analysis of intracellular interferon-gamma synthesis in rat CD4 T cells. Eur Cytokine Netw 9 613 618

64. NakanishiKKukitaF 1998 Functional synapses in synchronized bursting of neocortical neurons in culture. Brain Res 795 137 146

65. LiXZhouWZengSLiuMLuoQ 2007 Long-term recording on multi-electrode array reveals degraded inhibitory connection in neuronal network development. Biosens Bioelectron 22 1538 1543