Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation
of HCV-Specific CD8+ T Cells


The outcome of viral infections is dependent on the function of CD8+ T cells

which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4

(CD244) is a transmembrane protein belonging to the Ig superfamily which can

also be expressed by CD8+ T cells. The aim of this study was to analyze the

role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell

function and in particular to investigate its implication for exhaustion of

hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection.

We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells

during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to

both inhibition and activation of HCV-specific CD8+ T cell function,

depending on expression levels of 2B4 and the intracellular adaptor molecule SAP

and (iii) that 2B4 stimulation may counteract enhanced proliferation of

HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is

another important molecule within the network of costimulatory/inhibitory

receptors regulating CD8+ T cell function in acute and chronic hepatitis C

and that 2B4 expression levels could also be a marker of CD8+ T cell

dysfunction. Understanding in more detail how 2B4 exerts its differential

effects could have implications for the development of novel immunotherapies of

HCV infection aiming to achieve immune control.


Vyšlo v časopise: Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation of HCV-Specific CD8+ T Cells. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002045
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002045

Souhrn

The outcome of viral infections is dependent on the function of CD8+ T cells

which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4

(CD244) is a transmembrane protein belonging to the Ig superfamily which can

also be expressed by CD8+ T cells. The aim of this study was to analyze the

role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell

function and in particular to investigate its implication for exhaustion of

hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection.

We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells

during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to

both inhibition and activation of HCV-specific CD8+ T cell function,

depending on expression levels of 2B4 and the intracellular adaptor molecule SAP

and (iii) that 2B4 stimulation may counteract enhanced proliferation of

HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is

another important molecule within the network of costimulatory/inhibitory

receptors regulating CD8+ T cell function in acute and chronic hepatitis C

and that 2B4 expression levels could also be a marker of CD8+ T cell

dysfunction. Understanding in more detail how 2B4 exerts its differential

effects could have implications for the development of novel immunotherapies of

HCV infection aiming to achieve immune control.


Zdroje

1. WhitmireJKAhmedR

2000

Costimulation in antiviral immunity: differential requirements

for CD4(+) and CD8(+) T cell responses.

Curr Opin Immunol

12

448

455

2. SeeffLB

2002

Natural history of chronic hepatitis C.

Hepatology

36

S35

46

3. RehermannBNascimbeniM

2005

Immunology of hepatitis B virus and hepatitis C virus

infection.

Nat Rev Immunol

5

215

229

4. BowenDGWalkerCM

2005

Mutational escape from CD8+ T cell immunity: HCV evolution,

from chimpanzees to man.

J Exp Med

201

1709

1714

5. WedemeyerHHeXSNascimbeniMDavisARGreenbergHB

2002

Impaired effector function of hepatitis C virus-specific

CD8+ T cells in chronic hepatitis C virus infection.

J Immunol

169

3447

3458

6. GruenerNHLechnerFJungMCDiepolderHGerlachT

2001

Sustained dysfunction of antiviral CD8+ T lymphocytes after

infection with hepatitis C virus.

J Virol

75

5550

5558

7. GrakouiAShoukryNHWoollardDJHanJHHansonHL

2003

HCV persistence and immune evasion in the absence of memory T

cell help.

Science

302

659

662

8. ThimmeROldachDChangKMSteigerCRaySC

2001

Determinants of viral clearance and persistence during acute

hepatitis C virus infection.

J Exp Med

194

1395

1406

9. BarberDLWherryEJMasopustDZhuBAllisonJP

2006

Restoring function in exhausted CD8 T cells during chronic viral

infection.

Nature

439

682

687

10. WherryEJBlattmanJNMurali-KrishnaKvan der MostRAhmedR

2003

Viral persistence alters CD8 T-cell immunodominance and tissue

distribution and results in distinct stages of functional

impairment.

J Virol

77

4911

4927

11. KaufmannDEWalkerBD

2009

PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection

and the potential for therapeutic intervention.

J Immunol

182

5891

5897

12. RehermannB

2009

Hepatitis C virus versus innate and adaptive immune responses: a

tale of coevolution and coexistence.

J Clin Invest

119

1745

1754

13. NakamotoNKaplanDEColecloughJLiYValigaME

2008

Functional restoration of HCV-specific CD8 T cells by PD-1

blockade is defined by PD-1 expression and

compartmentalization.

Gastroenterology

134

1927

1937, 1937 e1921-1922

14. KasprowiczVSchulze Zur WieschJKuntzenTNolanBELongworthS

2008

High level of PD-1 expression on hepatitis C virus (HCV)-specific

CD8+ and CD4+ T cells during acute HCV infection, irrespective of

clinical outcome.

J Virol

82

3154

3160

15. WherryEJHaSJKaechSMHainingWNSarkarS

2007

Molecular signature of CD8+ T cell exhaustion during chronic

viral infection.

Immunity

27

670

684

16. McNerneyMEGuziorDKumarV

2005

2B4 (CD244)-CD48 interactions provide a novel MHC class

I-independent system for NK-cell self-tolerance in mice.

Blood

106

1337

1340

17. BrownMHBolesKvan der MerwePAKumarVMathewPA

1998

2B4, the natural killer and T cell immunoglobulin superfamily

surface protein, is a ligand for CD48.

J Exp Med

188

2083

2090

18. TangyeSGCherwinskiHLanierLLPhillipsJH

2000

2B4-mediated activation of human natural killer

cells.

Mol Immunol

37

493

501

19. NakajimaHCellaMLangenHFriedleinAColonnaM

1999

Activating interactions in human NK cell recognition: the role of

2B4-CD48.

Eur J Immunol

29

1676

1683

20. ChlewickiLKVelikovskyCABalakrishnanVMariuzzaRAKumarV

2008

Molecular basis of the dual functions of 2B4

(CD244).

J Immunol

180

8159

8167

21. MaCSNicholsKETangyeSG

2007

Regulation of cellular and humoral immune responses by the SLAM

and SAP families of molecules.

Annu Rev Immunol

25

337

379

22. BengschBSeigelBRuhlMTimmJKuntzM

2010

Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted

HCV-specific CD8+ T cells is linked to antigen recognition and T cell

differentiation.

PLoS Pathog

6

e1000947

23. UrbaniSAmadeiBTolaDPedrazziGSacchelliL

2008

Restoration of HCV-specific T cell functions by PD-1/PD-L1

blockade in HCV infection: effect of viremia levels and antiviral

treatment.

J Hepatol

48

548

558

24. PennaAPilliMZerbiniAOrlandiniAMezzadriS

2007

Dysfunction and functional restoration of HCV-specific CD8

responses in chronic hepatitis C virus infection.

Hepatology

45

588

601

25. BlackburnSDShinHHainingWNZouTWorkmanCJ

2009

Coregulation of CD8+ T cell exhaustion by multiple

inhibitory receptors during chronic viral infection.

Nat Immunol

10

29

37

26. ValianteNMTrinchieriG

1993

Identification of a novel signal transduction surface molecule on

human cytotoxic lymphocytes.

J Exp Med

178

1397

1406

27. BolesKSSteppSEBennettMKumarVMathewPA

2001

2B4 (CD244) and CS1: novel members of the CD2 subset of the

immunoglobulin superfamily molecules expressed on natural killer cells and

other leukocytes.

Immunol Rev

181

234

249

28. NakamotoNChoHShakedAOlthoffKValigaME

2009

Synergistic reversal of intrahepatic HCV-specific CD8 T cell

exhaustion by combined PD-1/CTLA-4 blockade.

PLoS Pathog

5

e1000313

29. WedemeyerHMizukoshiEDavisARBenninkJRRehermannB

2001

Cross-reactivity between hepatitis C virus and Influenza A virus

determinant-specific cytotoxic T cells.

J Virol

75

11392

11400

30. KasprowiczVKangYHLucasMSchulze zur WieschJKuntzenT

2010

Hepatitis C virus (HCV) sequence variation induces an

HCV-specific T-cell phenotype analogous to spontaneous

resolution.

J Virol

84

1656

1663

31. ChuangSSKimMHJohnsonLAAlbertssonPKitsonRP

2000

2B4 stimulation of YT cells induces natural killer cell cytolytic

function and invasiveness.

Immunology

100

378

383

32. KambayashiTAssarssonEChambersBJLjunggrenHG

2001

Cutting edge: Regulation of CD8(+) T cell proliferation by

2B4/CD48 interactions.

J Immunol

167

6706

6710

33. AltvaterBLandmeierSPschererSTemmeJJuergensH

2009

2B4 (CD244) signaling via chimeric receptors costimulates

tumor-antigen specific proliferation and in vitro expansion of human T

cells.

Cancer Immunol Immunother

58

1991

2001

34. RaziorrouhBSchrautWGerlachTNowackDGrünerNH

2010

The immunoregulatory role of CD244 in chronic hepatitis B

infection and its inhibitory potential on virus-specific CD8+ T-cell

function.

Hepatology

52

1934

1947

35. DongZCruz-MunozMEZhongMCChenRLatourS

2009

Essential function for SAP family adaptors in the surveillance of

hematopoietic cells by natural killer cells.

Nat Immunol

10

973

980

36. VeilletteA

2006

Immune regulation by SLAM family receptors and SAP-related

adaptors.

Nat Rev Immunol

6

56

66

37. ChenRRelouzatFRoncagalliRAoukatyATanR

2004

Molecular dissection of 2B4 signaling: implications for signal

transduction by SLAM-related receptors.

Mol Cell Biol

24

5144

5156

38. ShinHBlackburnSDIntlekoferAMKaoCAngelosantoJM

2009

A role for the transcriptional repressor Blimp-1 in CD8(+) T

cell exhaustion during chronic viral infection.

Immunity

31

309

320

39. Golden-MasonLPalmerBEKassamNTownshend-BulsonLLivingstonS

2009

Negative immune regulator Tim-3 is overexpressed on T cells in

hepatitis C virus infection and its blockade rescues dysfunctional CD4+

and CD8+ T cells.

J Virol

83

9122

9130

40. SuneethaPVSchlaphoffVWangCStegmannKAFytiliP

2009

Effect of peptide pools on effector functions of antigen-specific

CD8+ T cells.

J Immunol Methods

342

33

48

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


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