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Prolonged Antigen Presentation Is Required for Optimal CD8+ T Cell Responses against Malaria Liver Stage Parasites


Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization—a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages. Persisting antigen was detected in lymphoid organs and depends on the presence of CD11c+ cells. Prolonged antigen presentation enhanced the magnitude of the CD8+ T cell response in a number of ways. Firstly, reducing the time primed CD8+ T cells were exposed to antigen in vivo severely reduced the final size of the developing memory population. Secondly, fully developed memory cells expanded in previously immunized mice but not when transferred to naïve animals. Finally, persisting antigen was able to prime naïve cells, including recent thymic emigrants, to become functional effector cells capable of eliminating parasites in the liver. Together these data show that the optimal development of protective CD8+ T cell immunity against malaria liver stages is dependent upon the prolonged presentation of sporozoite-derived antigen.


Vyšlo v časopise: Prolonged Antigen Presentation Is Required for Optimal CD8+ T Cell Responses against Malaria Liver Stage Parasites. PLoS Pathog 6(5): e32767. doi:10.1371/journal.ppat.1000877
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000877

Souhrn

Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization—a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages. Persisting antigen was detected in lymphoid organs and depends on the presence of CD11c+ cells. Prolonged antigen presentation enhanced the magnitude of the CD8+ T cell response in a number of ways. Firstly, reducing the time primed CD8+ T cells were exposed to antigen in vivo severely reduced the final size of the developing memory population. Secondly, fully developed memory cells expanded in previously immunized mice but not when transferred to naïve animals. Finally, persisting antigen was able to prime naïve cells, including recent thymic emigrants, to become functional effector cells capable of eliminating parasites in the liver. Together these data show that the optimal development of protective CD8+ T cell immunity against malaria liver stages is dependent upon the prolonged presentation of sporozoite-derived antigen.


Zdroje

1. ClydeDF

1975 Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg 24 397 401

2. NussenzweigRS

VanderbergJ

MostH

OrtonC

1967 Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei. Nature 216 160 162

3. SchofieldL

VillaquiranJ

FerreiraA

SchellekensH

NussenzweigR

1987 Gamma interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites. Nature 330 664 666

4. WeissWR

SedegahM

BeaudoinRL

MillerLH

GoodMF

1988 CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc Natl Acad Sci U S A 85 573 576

5. SchellerLF

AzadAF

1995 Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoites. Proc Natl Acad Sci U S A 92 4066 4068

6. KaechSM

AhmedR

2001 Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat Immunol 2 415 422

7. van StipdonkMJ

LemmensEE

SchoenbergerSP

2001 Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol 2 423 429

8. MercadoR

VijhS

AllenSE

KerksiekK

PilipIM

2000 Early programming of T cell populations responding to bacterial infection. J Immunol 165 6833 6839

9. BevanMJ

FinkPJ

2001 The CD8 response on autopilot. Nat Immunol 2 381 382

10. DayCL

KaufmannDE

KiepielaP

BrownJA

MoodleyES

2006 PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 350 354

11. ZajacAJ

BlattmanJN

Murali-KrishnaK

SourdiveDJ

SureshM

1998 Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188 2205 2213

12. CallanMF

2003 The evolution of antigen-specific CD8+ T cell responses after natural primary infection of humans with Epstein-Barr virus. Viral Immunol 16 3 16

13. GillespieGM

WillsMR

AppayV

O'CallaghanC

MurphyM

2000 Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol 74 8140 8150

14. SnyderCM

ChoKS

BonnettEL

van DommelenS

ShellamGR

2008 Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29 650 659

15. VezysV

MasopustD

KemballCC

BarberDL

O'MaraLA

2006 Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J Exp Med 203 2263 2269

16. Jelley-GibbsDM

BrownDM

DibbleJP

HaynesL

EatonSM

2005 Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med 202 697 706

17. TurnerDL

CauleyLS

KhannaKM

LefrancoisL

2007 Persistent antigen presentation after acute vesicular stomatitis virus infection. J Virol 81 2039 2046

18. ZammitDJ

TurnerDL

KlonowskiKD

LefrancoisL

CauleyLS

2006 Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity 24 439 449

19. Jelley-GibbsDM

DibbleJP

BrownDM

StruttTM

McKinstryKK

2007 Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J Immunol 178 7563 7570

20. KhanZM

VanderbergJP

1991 Role of host cellular response in differential susceptibility of nonimmunized BALB/c mice to Plasmodium berghei and Plasmodium yoelii sporozoites. Infect Immun 59 2529 2534

21. BadovinacVP

HaringJS

HartyJT

2007 Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection. Immunity 26 827 841

22. PinschewerDD

OchsenbeinAF

OdermattB

BrinkmannV

HengartnerH

2000 FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 164 5761 5770

23. ChakravartyS

CockburnIA

KukS

OverstreetMG

SacciJB

2007 CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nat Med 13 1035 1041

24. JungS

UnutmazD

WongP

SanoG

De los SantosK

2002 In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17 211 220

25. van RooijenN

SandersA

van den BergTK

1996 Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J Immunol Methods 193 93 99

26. Asselin-PaturelC

BrizardG

PinJJ

BriereF

TrinchieriG

2003 Mouse strain differences in plasmacytoid dendritic cell frequency and function revealed by a novel monoclonal antibody. J Immunol 171 6466 6477

27. AllanRS

WaithmanJ

BedouiS

JonesCM

VilladangosJA

2006 Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25 153 162

28. ChenJ

TrounstineM

AltFW

YoungF

KuraharaC

1993 Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol 5 647 656

29. NusslerA

FollezouJY

MiltgenF

MazierD

1989 Effect of irradiation on Plasmodium sporozoites depends on the species of hepatocyte infected. Trop Med Parasitol 40 468 469

30. SilvieO

SemblatJP

FranetichJF

HannounL

ElingW

2002 Effects of irradiation on Plasmodium falciparum sporozoite hepatic development: implications for the design of pre-erythrocytic malaria vaccines. Parasite Immunol 24 221 223

31. SykulevY

JooM

VturinaI

TsomidesTJ

EisenHN

1996 Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 4 565 571

32. BerenzonD

SchwenkRJ

LetellierL

Guebre-XabierM

WilliamsJ

2003 Protracted protection to Plasmodium berghei malaria is linked to functionally and phenotypically heterogeneous liver memory CD8+ T cells. J Immunol 171 2024 2034

33. MuellerAK

DeckertM

HeissK

GoetzK

MatuschewskiK

2007 Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cells. Am J Pathol 171 107 115

34. BelnoueE

CostaFT

FrankenbergT

VigarioAM

VozaT

2004 Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatment. J Immunol 172 2487 2495

35. HafallaJC

SanoG

CarvalhoLH

MorrotA

ZavalaF

2002 Short-term antigen presentation and single clonal burst limit the magnitude of the CD8(+) T cell responses to malaria liver stages. Proc Natl Acad Sci U S A 99 11819 11824

36. LeiriaoP

MotaMM

RodriguezA

2006 Reply to Rénia et al. The Journal of Infectious Diseases 193 164 165

37. PutriantiED

SilvieO

KordesM

BorrmannS

MatuschewskiK

2009 Vaccine-like immunity against malaria by repeated causal-prophylactic treatment of liver-stage Plasmodium parasites. J Infect Dis 199 899 903

38. TaylorWR

WhiteNJ

2004 Antimalarial drug toxicity: a review. Drug Saf 27 25 61

39. RomeroP

MaryanskiJL

CorradinG

NussenzweigRS

NussenzweigV

1989 Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341 323 326

40. HafallaJC

RaiU

MorrotA

Bernal-RubioD

ZavalaF

2006 Priming of CD8+ T cell responses following immunization with heat-killed Plasmodium sporozoites. Eur J Immunol 36 1179 1186

41. HaySI

RogersDJ

ToomerJF

SnowRW

2000 Annual Plasmodium falciparum entomological inoculation rates (EIR) across Africa: literature survey, Internet access and review. Trans R Soc Trop Med Hyg 94 113 127

42. BilsboroughJ

CarlisleM

GoodMF

1993 Identification of Caucasian CD4 T cell epitopes on the circumsporozoite protein of Plasmodium vivax. T cell memory. J Immunol 151 890 899

43. ZeveringY

KhamboonruangC

RungruengthanakitK

TungviboonchaiL

RuengpipattanapanJ

1994 Life-spans of human T-cell responses to determinants from the circumsporozoite proteins of Plasmodium falciparum and Plasmodium vivax. Proc Natl Acad Sci U S A 91 6118 6122

44. DoolanDL

HoffmanSL

SouthwoodS

WentworthPA

SidneyJ

1997 Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. Immunity 7 97 112

45. CockburnIA

ChakravartyS

OverstreetMG

Garcia-SastreA

ZavalaF

2008 Memory CD8+ T cell responses expand when antigen presentation overcomes T cell self-regulation. J Immunol 180 64 71

46. KhannaKM

AguilaCC

RedmanJM

Suarez-RamirezJE

LefrancoisL

2008 In situ imaging reveals different responses by naive and memory CD8 T cells to late antigen presentation by lymph node DC after influenza virus infection. Eur J Immunol 38 3304 3315

47. ProbstHC

TschannenK

OdermattB

SchwendenerR

ZinkernagelRM

2005 Histological analysis of CD11c-DTR/GFP mice after in vivo depletion of dendritic cells. Clin Exp Immunol 141 398 404

48. BelzGT

SmithCM

KleinertL

ReadingP

BrooksA

2004 Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci U S A 101 8670 8675

49. InabaK

TurleyS

YamaideF

IyodaT

MahnkeK

1998 Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med 188 2163 2173

50. LeeJW

EpardaudM

SunJ

BeckerJE

ChengAC

2007 Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 8 181 190

51. GonzalezM

MackayF

BrowningJL

Kosco-VilboisMH

NoelleRJ

1998 The sequential role of lymphotoxin and B cells in the development of splenic follicles. J Exp Med 187 997 1007

52. FuYX

HuangG

WangY

ChaplinDD

1998 B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin alpha-dependent fashion. J Exp Med 187 1009 1018

53. KamathAT

HenriS

BattyeF

ToughDF

ShortmanK

2002 Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100 1734 1741

54. SanoG

HafallaJC

MorrotA

AbeR

LafailleJJ

2001 Swift development of protective effector functions in naive CD8(+) T cells against malaria liver stages. J Exp Med 194 173 180

55. Bruna-RomeroO

HafallaJC

Gonzalez-AseguinolazaG

SanoG

TsujiM

2001 Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. Int J Parasitol 31 1499 1502

56. ZammitDJ

CauleyLS

PhamQM

LefrancoisL

2005 Dendritic cells maximize the memory CD8 T cell response to infection. Immunity 22 561 570

57. MasopustD

VezysV

MarzoAL

LefrancoisL

2001 Preferential localization of effector memory cells in nonlymphoid tissue. Science 291 2413 2417

58. BarnesE

WardSM

KasprowiczVO

DusheikoG

KlenermanP

2004 Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells. Eur J Immunol 34 1570 1577

59. ObarJJ

KhannaKM

LefrancoisL

2008 Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28 859 869

60. ScribaTJ

PurbhooM

DayCL

RobinsonN

FidlerS

2005 Ultrasensitive detection and phenotyping of CD4+ T cells with optimized HLA class II tetramer staining. J Immunol 175 6334 6343

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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