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
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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