#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Th2-polarised PrP-specific Transgenic T-cells Confer Partial Protection against Murine Scrapie


Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes.


Vyšlo v časopise: Th2-polarised PrP-specific Transgenic T-cells Confer Partial Protection against Murine Scrapie. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002216
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002216

Souhrn

Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes.


Zdroje

1. AguzziACalellaAM 2009 Prions: protein aggregation and infectious diseases. Physiol Rev 89 1105 1152

2. PrusinerSB 1998 Prions. Proc Natl Acad Sci U S A 95 13363 13383

3. HeppnerFLMusahlCArrighiIKleinMARulickeT 2001 Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294 178 182

4. WhiteAREneverPTayebiMMushensRLinehanJ 2003 Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422 80 83

5. ZuberCMittereggerGPaceCZerrIKretzschmarHA 2007 Anti-LRP/LR antibody W3 hampers peripheral PrPSc propagation in scrapie infected mice. Prion 1 207 212

6. GoniFPrelliFSchreiberFScholtzovaHChungE 2008 High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153 679 686

7. SacquinABergotASAucouturierPBruley-RossetM 2008 Contribution of antibody and T cell-specific responses to the progression of 139A-scrapie in C57BL/6 mice immunized with prion protein peptides. J Immunol 181 768 775

8. SchwarzAKratkeOBurwinkelMRiemerCSchultzJ 2003 Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent. Neurosci Lett 350 187 189

9. GregoireSBergotASFeraudetCCarnaudCAucouturierP 2005 The murine B cell repertoire is severely selected against endogenous cellular prion protein. J Immunol 175 6443 6449

10. PolymenidouMHeppnerFLPellicioliECUrichEMieleG 2004 Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc Natl Acad Sci U S A 101 Suppl 2 14670 14676

11. CarnaudCBachyV 2010 Cell-based immunotherapy of prion diseases by adoptive transfer of antigen-loaded dendritic cells or antigen-primed CD4+ T lymphocytes. Prion 4 66 71

12. BachyVBalleriniCGourdainPPrignonAIkenS 2010 Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie. J Gen Virol 91 809 820

13. GourdainPGregoireSIkenSBachyVDorbanG 2009 Adoptive transfer of T lymphocytes sensitized against the prion protein attenuates prion invasion in scrapie-infected mice. J Immunol 183 6619 6628

14. TehHSKishiHScottBBorgulyaPvon BoehmerH 1990 Early deletion and late positive selection of T cells expressing a male-specific receptor in T-cell receptor transgenic mice. Dev Immunol 1 1 10

15. KilleenNDavisCBChuKCrooksMESawadaS 1993 CD4 function in thymocyte differentiation and T cell activation. Philos Trans R Soc Lond B Biol Sci 342 25 34

16. BillJKanagawaOLintenJUtsunomiyaYPalmerE 1990 Class I and class II MHC gene products differentially affect the fate of V beta 5 bearing thymocytes. J Mol Cell Immunol : 4 269 279; discussion 279–280

17. SakaguchiS 2004 Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22 531 562

18. GregoireSLogreCMetharomPLoingEChomilierJ 2004 Identification of two immunogenic domains of the prion protein–PrP–which activate class II-restricted T cells and elicit antibody responses against the native molecule. J Leukoc Biol 76 125 134

19. DillonSRJamesonSCFinkPJ 1994 V beta 5+ T cell receptors skew toward OVA+H-2Kb recognition. J Immunol 152 1790 1801

20. EnariMFlechsigEWeissmannC 2001 Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A 98 9295 9299

21. PeretzDWilliamsonRAKanekoKVergaraJLeclercE 2001 Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412 739 743

22. SigurdssonEMSyMSLiRScholtzovaHKascsakRJ 2003 Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci Lett 336 185 187

23. WojteraMSikorskaBSobowTLiberskiPP 2005 Microglial cells in neurodegenerative disorders. Folia Neuropathol 43 311 321

24. OrgogozoJMGilmanSDartiguesJFLaurentBPuelM 2003 Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61 46 54

25. SchwartzMShechterR 2010 Systemic inflammatory cells fight off neurodegenerative disease. Nat Rev Neurol 6 405 410

26. Acha-OrbeaHMitchellDJTimmermannLWraithDCTauschGS 1988 Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54 263 273

27. HochgeschwenderUWeltzienHUEichmannKWallaceRBEpplenJT 1986 Preferential expression of a defined T-cell receptor beta-chain gene in hapten-specific cytotoxic T-cell clones. Nature 322 376 378

28. YanagiYMaekawaRCookTKanagawaOOldstoneMB 1990 Restricted V-segment usage in T-cell receptors from cytotoxic T lymphocytes specific for a major epitope of lymphocytic choriomeningitis virus. J Virol 64 5919 5926

29. BrandleDBurkiKWallaceVARohrerUHMakTW 1991 Involvement of both T cell receptor V alpha and V beta variable region domains and alpha chain junctional region in viral antigen recognition. Eur J Immunol 21 2195 2202

30. VerdaguerJYoonJWAndersonBAverillNUtsugiT 1996 Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains. J Immunol 157 4726 4735

31. YokosukaTTakaseKSuzukiMNakagawaYTakiS 2002 Predominant role of T cell receptor (TCR)-alpha chain in forming preimmune TCR repertoire revealed by clonal TCR reconstitution system. J Exp Med 195 991 1001

32. BlackmanMASmithHPLePWoodlandDL 1993 Influence of the T cell receptor alpha-chain on T cell reactivity and tolerance to Mls-1 in T cell receptor beta-chain transgenic mice. J Immunol 151 556 565

33. FreitasAARochaB 1999 Peripheral T cell survival. Curr Opin Immunol 11 152 156

34. BalleriniCGourdainPBachyVBlanchardNLevavasseurE 2006 Functional implication of cellular prion protein in antigen-driven interactions between T cells and dendritic cells. J Immunol 176 7254 7262

35. HeikenwalderMPolymenidouMJuntTSigurdsonCWagnerH 2004 Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 10 187 192

36. MabbottNAMackayFMinnsFBruceME 2000 Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nat Med 6 719 720

37. MontrasioFFriggRGlatzelMKleinMAMackayF 2000 Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288 1257 1259

38. RaymondCRAucouturierPMabbottNA 2007 In vivo depletion of CD11c+ cells impairs scrapie agent neuroinvasion from the intestine. J Immunol 179 7758 7766

39. AucouturierPGeissmannFDamotteDSaborioGPMeekerHC 2001 Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest 108 703 708

40. BeringueVCouvreurPDormontD 2002 Involvement of macrophages in the pathogenesis of transmissible spongiform encephalopathies. Dev Immunol 9 19 27

41. CarpRICallahanSM 1982 Effect of mouse peritoneal macrophages on scrapie infectivity during extended in vitro incubation. Intervirology 17 201 207

42. BeringueVLe DurATixadorPReineFLepourryL 2008 Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS ONE 3 e1419

43. LoeuilletCLemaire-VieilleCNaquetPCesbron-DelauwMFGagnonJ 2010 Prion replication in the hematopoietic compartment is not required for neuroinvasion in scrapie mouse model. PLoS ONE 5 e13166

44. DereckiNCCardaniANYangCHQuinniesKMCrihfieldA 2010 Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207 1067 1080

45. ShechterRLondonAVarolCRaposoCCusimanoM 2009 Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6 e1000113

46. ZivYRonNButovskyOLandaGSudaiE 2006 Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9 268 275

47. FalsigJJuliusCMargalithISchwarzPHeppnerFL 2008 A versatile prion replication assay in organotypic brain slices. Nat Neurosci 11 109 117

48. SandbergMKAl-DoujailyHSharpsBClarkeARCollingeJ 2011 Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470 540 542

49. ButovskyOLandaGKunisGZivYAvidanH 2006 Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116 905 915

50. ChaoCCHuSPetersonPK 1995 Modulation of human microglial cell superoxide production by cytokines. J Leukoc Biol 58 65 70

51. PonomarevEDMareszKTanYDittelBN 2007 CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27 10714 10721

52. BuelerHFischerMLangYBluethmannHLippHP 1992 Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356 577 582

53. PannetierCCochetMDarcheSCasrougeAZollerM 1993 The sizes of the CDR3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci U S A 90 4319 4323

54. LimABaronVFerradiniLBonnevilleMKourilskyP 2002 Combination of MHC-peptide multimer-based T cell sorting with the Immunoscope permits sensitive ex vivo quantitation and follow-up of human CD8+ T cell immune responses. J Immunol Methods 261 177 194

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2011 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

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#