#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Peptides Presented by HLA-E Molecules Are Targets for Human CD8 T-Cells with Cytotoxic as well as Regulatory Activity


Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8+ T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8+ T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8+ T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-β. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8+ T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity.


Vyšlo v časopise: Peptides Presented by HLA-E Molecules Are Targets for Human CD8 T-Cells with Cytotoxic as well as Regulatory Activity. PLoS Pathog 6(2): e32767. doi:10.1371/journal.ppat.1000782
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000782

Souhrn

Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8+ T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8+ T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8+ T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-β. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8+ T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity.


Zdroje

1. World Health Organization 2004 Global Tuberculosis Control. WHO report, WHO, Geneva

2. FinePE

RodriguesLC

1990 Modern vaccines. Mycobacterial diseases. Lancet 335 1016 1020

3. OttenhoffTH

2009 Overcoming the global crisis: “yes, we can”, but also for TB …? Eur J Immunol 39 2014 2020

4. KaufmannSH

2006 Envisioning future strategies for vaccination against tuberculosis. Nat Rev Immunol 6 699 704

5. KaufmannSH

2001 How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 1 20 30

6. Anthony Nolan Research Institute 2009 HLA class I and class II sequence alignments, June 2009 updates. http://www.anthonynolan.org.uk/research/hlainformaticsgroup (2009)

7. PietraG

RomagnaniC

MazzarinoP

FalcoM

MilloE

2003 HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes. Proc Natl Acad Sci U S A 100 10896 10901

8. MazzarinoP

PietraG

VaccaP

FalcoM

ColauD

2005 Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion. Eur J Immunol 35 3240 3247

9. Salerno-GoncalvesR

Fernandez-VinaM

LewinsohnDM

SzteinMB

2004 Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine. J Immunol 173 5852 5862

10. LiJ

GoldsteinI

Glickman-NirE

JiangH

ChessL

2001 Induction of TCR Vbeta-specific CD8+ CTLs by TCR Vbeta-derived peptides bound to HLA-E. J Immunol 167 3800 3808

11. StrongRK

HolmesMA

LiP

BraunL

LeeN

2003 HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. J Biol Chem 278 5082 5090

12. GrimsleyC

OberC

1997 Population genetic studies of HLA-E: evidence for selection. Hum Immunol 52 33 40

13. HeinzelAS

GrotzkeJE

LinesRA

LewinsohnDA

McNabbAL

2002 HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J Exp Med 196 1473 1481

14. DaftaryA

PadayatchiN

PadillaM

2007 HIV testing and disclosure: a qualitative analysis of TB patients in South Africa. AIDS Care 19 572 577

15. CollinsKL

ChenBK

KalamsSA

WalkerBD

BaltimoreD

1998 HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391 397 401

16. CohenGB

GandhiRT

DavisDM

MandelboimO

ChenBK

1999 The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10 661 671

17. NoursadeghiM

KatzDR

MillerRF

2006 HIV-1 infection of mononuclear phagocytic cells: the case for bacterial innate immune deficiency in AIDS. Lancet Infect Dis 6 794 804

18. PietraG

RomagnaniC

FalcoM

VitaleM

CastriconiR

2001 The analysis of the natural killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR alpha/beta-mediated recognition. Eur J Immunol 31 3687 3693

19. GarciaP

LlanoM

de HerediaAB

WillbergCB

CaparrosE

2002 Human T cell receptor-mediated recognition of HLA-E. Eur J Immunol 32 936 944

20. MillerJD

WeberDA

IbegbuC

PohlJ

AltmanJD

2003 Analysis of HLA-E peptide-binding specificity and contact residues in bound peptide required for recognition by CD94/NKG2. J Immunol 171 1369 1375

21. HoareHL

SullivanLC

PietraG

ClementsCS

LeeEJ

2006 Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat Immunol 7 256 264

22. SullivanBA

KrajP

WeberDA

IgnatowiczL

JensenPE

2002 Positive selection of a Qa-1-restricted T cell receptor with specificity for insulin. Immunity 17 95 105

23. SarantopoulosS

LuL

CantorH

2004 Qa-1 restriction of CD8+ suppressor T cells. J Clin Invest 114 1218 1221

24. JiangH

ChessL

2008 Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: An essay on peripheral T-cell regulation. Hum Immunol 69 721 727

25. DoytchinovaIA

FlowerDR

2007 Predicting class I major histocompatibility complex (MHC) binders using multivariate statistics: comparison of discriminant analysis and multiple linear regression. J Chem Inf Model 47 234 238

26. SandbergM

ErikssonL

JonssonJ

SjostromM

WoldS

1998 New chemical descriptors relevant for the design of biologically active peptides. A multivariate characterization of 87 amino acids. J Med Chem 41 2481 2491

27. HellbergS

SjostromM

SkagerbergB

WoldS

1987 Peptide quantitative structure-activity relationships, a multivariate approach. J Med Chem 30 1126 1135

28. BraudVM

AllanDS

O'CallaghanCA

SoderstromK

D'AndreaA

1998 HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391 795 799

29. CaccamoN

GugginoG

MeravigliaS

GelsominoG

DiCP

2009 Analysis of Mycobacterium tuberculosis-specific CD8 T-cells in patients with active tuberculosis and in individuals with latent infection. PLoS ONE 4 e5528 doi:10.1371/journal.pone.0005528

30. WhittakerE

KampmannB

2008 Perinatal tuberculosis: new challenges in the diagnosis and treatment of tuberculosis in infants and the newborn. Early Hum Dev 84 795 799

31. OttenhoffTH

MutisT

1990 Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man. J Exp Med 171 2011 2024

32. JoostenSA

van MeijgaardenKE

SavageND

de BoerT

TriebelF

2007 Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc Natl Acad Sci U S A 104 8029 8034

33. GelukA

van MeijgaardenKE

JansonAA

DrijfhoutJW

MeloenRH

1992 Functional analysis of DR17(DR3)-restricted mycobacterial T cell epitopes reveals DR17-binding motif and enables the design of allele-specific competitor peptides. J Immunol 149 2864 2871

34. BodenE

TangQ

Bour-JordanH

BluestoneJA

2003 The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp 252 55 63

35. NocentiniG

RonchettiS

CuzzocreaS

RiccardiC

2007 GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol 37 1165 1169

36. SavageND

de BoerT

WalburgKV

JoostenSA

van MeijgaardenK

2008 Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol 181 2220 2226

37. NakamuraK

KitaniA

StroberW

2001 Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194 629 644

38. SaharinenJ

HyytiainenM

TaipaleJ

Keski-OjaJ

1999 Latent transforming growth factor-beta binding proteins (LTBPs)–structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev 10 99 117

39. OttenhoffTH

HaanenJB

GelukA

MutisT

AbBK

1991 Regulation of mycobacterial heat-shock protein-reactive T cells by HLA class II molecules: lessons from leprosy. Immunol Rev 121 171 191

40. GrotzkeJE

HarriffMJ

SilerAC

NoltD

DelepineJ

2009 The Mycobacterium tuberculosis phagosome is a HLA-I processing competent organelle. PLoS Pathog 5 e1000374 doi:10.1371/journal.ppat.1000374

41. LinMY

ReddyTB

ArendSM

FriggenAH

FrankenKL

2009 Cross-reactive immunity to Mycobacterium tuberculosis DosR-regulon encoded antigens in individuals infected with environmental, non-tuberculous mycobacteria. Infect Immun 77 5071 5079

42. HuD

IkizawaK

LuL

SanchiricoME

ShinoharaML

2004 Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol 5 516 523

43. KursarM

KochM

MittruckerHW

NouaillesG

BonhagenK

2007 Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis. J Immunol 178 2661 2665

44. Scott-BrowneJP

ShafianiS

Tucker-HeardG

Ishida-TsubotaK

FontenotJD

2007 Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med 204 2159 2169

45. ChenX

ZhouB

LiM

DengQ

WuX

2007 CD4(+)CD25(+)FoxP3(+) regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin Immunol 123 50 59

46. Guyot-RevolV

InnesJA

HackforthS

HinksT

LalvaniA

2005 Regulatory T Cells are Expanded in Blood and Disease Sites in Tuberculosis Patients. Am J Respir Crit Care Med 173 803 810

47. Ribeiro-RodriguesR

ResendeCT

RojasR

ToossiZ

DietzeR

2006 A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol 144 25 34

48. HougardyJM

PlaceS

HildebrandM

DrowartA

DebrieAS

2007 Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med 176 409 416

49. LundJM

HsingL

PhamTT

RudenskyAY

2008 Coordination of early protective immunity to viral infection by regulatory T cells. Science 320 1220 1224

50. IshitaniA

SageshimaN

HatakeK

2006 The involvement of HLA-E and -F in pregnancy. J Reprod Immunol 69 101 113

51. TilburgsT

RoelenDL

van der MastBJ

van SchipJJ

KleijburgC

2006 Differential distribution of CD4(+)CD25(bright) and CD8(+)CD28(−) T-cells in decidua and maternal blood during human pregnancy. Placenta 27 Suppl A S47 S53

52. ShaoL

JacobsAR

JohnsonVV

MayerL

2005 Activation of CD8+ regulatory T cells by human placental trophoblasts. J Immunol 174 7539 7547

53. GuanP

DoytchinovaIA

WalsheVA

BorrowP

FlowerDR

2005 Analysis of peptide-protein binding using amino acid descriptors: prediction and experimental verification for human histocompatibility complex HLA-A0201. J Med Chem 48 7418 7425

54. FlowerDR

1998 DISSIM: a program for the analysis of chemical diversity. J Mol Graph Model 16 239 53 264

55. HiemstraHS

DuinkerkenG

BenckhuijsenWE

AmonsR

de VriesRR

1997 The identification of CD4+ T cell epitopes with dedicated synthetic peptide libraries. Proc Natl Acad Sci U S A 94 10313 10318

56. TeixeiraA

BenckhuijsenWE

de KoningPE

ValentijnAR

DrijfhoutJW

2002 The use of DODT as a non-malodorous scavenger in Fmoc-based peptide synthesis. Protein Pept Lett 9 379 385

57. GelukA

van MeijgaardenKE

FrankenKL

DrijfhoutJW

D'SouzaS

2000 Identification of major epitopes of Mycobacterium tuberculosis AG85B that are recognized by HLA-A*0201-restricted CD8+ T cells in HLA-transgenic mice and humans. J Immunol 165 6463 6471

58. LeytenEM

ArendSM

PrinsC

CobelensFG

OttenhoffTH

2007 Discrepancy between Mycobacterium tuberculosis-specific gamma interferon release assays using short and prolonged in vitro incubation. Clin Vaccine Immunol 14 880 885

59. UlbrechtM

MartinozziS

GrzeschikM

HengelH

EllwartJW

2000 Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J Immunol 164 5019 5022

60. OttenhoffTH

Kale AbB

van EmbdenJD

TholeJE

KiesslingR

1988 The recombinant 65-kD heat shock protein of Mycobacterium bovis Bacillus Calmette-Guerin/M. tuberculosis is a target molecule for CD4+ cytotoxic T lymphocytes that lyse human monocytes. J Exp Med 168 1947 1952

61. van ElsCA

D'AmaroJ

PoolJ

BloklandE

BakkerA

1992 Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance. Immunogenetics 35 161 165

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 2
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#