The Human Cytomegalovirus UL11 Protein Interacts with the Receptor Tyrosine Phosphatase CD45, Resulting in Functional Paralysis of T Cells

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Human cytomegalovirus (CMV) exerts diverse and complex effects on the immune system, not all of which have been attributed to viral genes. Acute CMV infection results in transient restrictions in T cell proliferative ability, which can impair the control of the virus and increase the risk of secondary infections in patients with weakened or immature immune systems. In a search for new immunomodulatory proteins, we investigated the UL11 protein, a member of the CMV RL11 family. This protein family is defined by the RL11 domain, which has homology to immunoglobulin domains and adenoviral immunomodulatory proteins. We show that pUL11 is expressed on the cell surface and induces intercellular interactions with leukocytes. This was demonstrated to be due to the interaction of pUL11 with the receptor tyrosine phosphatase CD45, identified by mass spectrometry analysis of pUL11-associated proteins. CD45 expression is sufficient to mediate the interaction with pUL11 and is required for pUL11 binding to T cells, indicating that pUL11 is a specific CD45 ligand. CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off. In the presence of pUL11, several CD45-mediated functions were inhibited. The induction of tyrosine phosphorylation of multiple signaling proteins upon TCR stimulation was reduced and T cell proliferation was impaired. We therefore conclude that pUL11 has immunosuppressive properties, and that disruption of T cell function via inhibition of CD45 is a previously unknown immunomodulatory strategy of CMV.

Vyšlo v časopise: The Human Cytomegalovirus UL11 Protein Interacts with the Receptor Tyrosine Phosphatase CD45, Resulting in Functional Paralysis of T Cells. PLoS Pathog 7(12): e32767. doi:10.1371/journal.ppat.1002432
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002432

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1. MocarskiEShenkTPassR 2007 Cytomegaloviruses. KnipeDMHowleyPM Fields' Virology 5th Edition Philadelphia (PA) Lippincott, Williams and Wilkins 2702 2772

2. JacksonSEMasonGMWillsMR 2011 Human cytomegalovirus immunity and immune evasion. Virus Res 157 151 160

3. WilkinsonGWTomasecPStantonRJArmstrongMProd'hommeV 2008 Modulation of natural killer cells by human cytomegalovirus. J Clin Virol 41 206 212

4. GörzerIKerschnerHRedlberger-FritzMPuchhammer-StöcklE 2010 Human cytomegalovirus (HCMV) genotype populations in immunocompetent individuals during primary HCMV infection. J Clin Virol 48 100 103

5. Meyer-KönigUEbertKSchrageBPollakSHufertFT 1998 Simultaneous infection of healthy people with multiple human cytomegalovirus strains. Lancet 352 1280 1281

6. RossSAAroraNNovakZFowlerKBBrittWJ 2010 Cytomegalovirus reinfections in healthy seroimmune women. J Infect Dis 201 386 389

7. PowersCDeFilippisVMalouliDFrühK 2008 Cytomegalovirus immune evasion. Curr Top Microbiol Immunol 325 333 359

8. BrittW 2008 Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol 325 417 470

9. CarneyWPHirschMS 1981 Mechanisms of immunosuppression in cytomegalovirus mononucleosis. II. Virus-monocyte interactions. J Infect Dis 144 47 54

10. CarneyWPRubinRHHoffmanRAHansenWPHealeyK 1981 Analysis of T lymphocyte subsets in cytomegalovirus mononucleosis. J Immunol 126 2114 2116

11. GiebelSMaccarioRLilleriDZeccaMAvanziniMA 2005 The immunosuppressive effect of human cytomegalovirus infection in recipients of allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 36 503 509

12. RinaldoCRJrCarneyWPRichterBSBlackPHHirschMS 1980 Mechanisms of immunosuppression in cytomegaloviral mononucleosis. J Infect Dis 141 488 495

13. TuWChenSSharpMDekkerCManganelloAM 2004 Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children. J Immunol 172 3260 3267

14. HirschMSFelsensteinD 1984 Cytomegalovirus-induced immunosuppression. Ann N Y Acad Sci 437 8 15

15. SiaIGPatelR 2000 New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 13 83 121 table

16. BastaSBenninkJR 2003 A survival game of hide and seek: cytomegaloviruses and MHC class I antigen presentation pathways. Viral Immunol 16 231 242

17. KotenkoSVSaccaniSIzotovaLSMirochnitchenkoOVPestkaS 2000 Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci U S A 97 1695 1700

18. MichelsonSAlcamiJKimSJDanielpourDBachelerieF 1994 Human cytomegalovirus infection induces transcription and secretion of transforming growth factor beta 1. J Virol 68 5730 5737

19. SenechalBBoruchovAMReaganJLHartDNYoungJW 2004 Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103 4207 4215

20. SpencerJVLockridgeKMBarryPALinGTsangM 2002 Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76 1285 1292

21. RafteryMJSchwabMEibertSMSamstagYWalczakH 2001 Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 15 997 1009

22. BarclayAN 2003 Membrane proteins with immunoglobulin-like domains - a master superfamily of interaction molecules. Semin Immunol 15 215 223

23. GewurzBEGaudetRTortorellaDWangEWPloeghHL 2001 Virus subversion of immunity: a structural perspective. Curr Opin Immunol 13 442 450

24. SmithHRHeuselJWMehtaIKKimSDornerBG 2002 Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci U S A 99 8826 8831

25. DolanACunninghamCHectorRDHassan-WalkerAFLeeL 2004 Genetic content of wild-type human cytomegalovirus. J Gen Virol 85 1301 1312

26. DavisonAJAkterPCunninghamCDolanAAddisonC 2003 Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes. J Gen Virol 84 657 663

27. AtalayRZimmermannAWagnerMBorstEBenzC 2002 Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcgamma receptor homologs. J Virol 76 8596 8608

28. LilleyBNPloeghHLTirabassiRS 2001 Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. J Virol 75 11218 11221

29. HitomiSKozuka-HataHChenZSuganoSYamaguchiN 1997 Human cytomegalovirus open reading frame UL11 encodes a highly polymorphic protein expressed on the infected cell surface. Arch Virol 142 1407 1427

30. TimonMArnaiz-VillenaARuiz-ContrerasJRamos-AmadorJTPachecoA 1993 Selective impairment of T lymphocyte activation through the T cell receptor/CD3 complex after cytomegalovirus infection. Clin Exp Immunol 94 38 42

31. CaleCMKleinNJNovelliVVeysPJonesAM 1997 Severe combined immunodeficiency with abnormalities in expression of the common leucocyte antigen, CD45. Arch Dis Child 76 163 164

32. KungCPingelJTHeikinheimoMKlemolaTVarkilaK 2000 Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med 6 343 345

33. TchilianEZWallaceDLWellsRSFlowerDRMorganG 2001 A deletion in the gene encoding the CD45 antigen in a patient with SCID. J Immunol 166 1308 1313

34. BythKFConroyLAHowlettSSmithAJMayJ 1996 CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation. J Exp Med 183 1707 1718

35. KishiharaKPenningerJWallaceVAKündigTMKawaiK 1993 Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74 143 156

36. MeePJTurnerMBassonMACostelloPSZamoyskaR 1999 Greatly reduced efficiency of both positive and negative selection of thymocytes in CD45 tyrosine phosphatase-deficient mice. Eur J Immunol 29 2923 2933

37. StoneJDConroyLABythKFHedererRAHowlettS 1997 Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70. J Immunol 158 5773 5782

38. BarberEKDasguptaJDSchlossmanSFTrevillyanJMRuddCE 1989 The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc Natl Acad Sci U S A 86 3277 3281

39. van OersNSKilleenNWeissA 1996 Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. J Exp Med 183 1053 1062

40. SalmondRJFilbyAQureshiICasertaSZamoyskaR 2009 T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev 228 9 22

41. AmreinKESeftonBM 1988 Mutation of a site of tyrosine phosphorylation in the lymphocyte-specific tyrosine protein kinase, p56lck, reveals its oncogenic potential in fibroblasts. Proc Natl Acad Sci U S A 85 4247 4251

42. EckMJAtwellSKShoelsonSEHarrisonSC 1994 Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature 368 764 769

43. MarthJDCooperJAKingCSZieglerSFTinkerDA 1988 Neoplastic transformation induced by an activated lymphocyte-specific protein tyrosine kinase (pp56lck). Mol Cell Biol 8 540 550

44. OstergaardHLShackelfordDAHurleyTRJohnsonPHymanR 1989 Expression of CD45 alters phosphorylation of the lck-encoded tyrosine protein kinase in murine lymphoma T-cell lines. Proc Natl Acad Sci U S A 86 8959 8963

45. XuHLittmanDR 1995 The kinase-dependent function of Lck in T-cell activation requires an intact site for tyrosine autophosphorylation. Ann N Y Acad Sci 766 99 116

46. YamaguchiHHendricksonWA 1996 Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 384 484 489

47. BakerMGambleJToozeRHigginsDYangFT 2000 Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice. EMBO J 19 4644 4654

48. D'OroUSakaguchiKAppellaEAshwellJD 1996 Mutational analysis of Lck in CD45-negative T cells: dominant role of tyrosine 394 phosphorylation in kinase activity. Mol Cell Biol 16 4996 5003

49. McNeillLSalmondRJCooperJCCarretCKCassady-CainRL 2007 The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity 27 425 437

50. HermistonMLXuZWeissA 2003 CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 21 107 137

51. StantonRJMcSharryBPArmstrongMTomasecPWilkinsonGW 2008 Re-engineering adenovirus vector systems to enable high-throughput analyses of gene function. Biotechniques 45 659 8

52. SinzgerCHahnGDigelMKatonaRSampaioKL 2008 Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J Gen Virol 89 359 368

53. IrlesCSymonsAMichelFBakkerTRvan der MerwePA 2003 CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nat Immunol 4 189 197

54. van VlietSJGringhuisSIGeijtenbeekTBvan KooykY 2006 Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45. Nat Immunol 7 1200 1208

55. ThomasML 1989 The leukocyte common antigen family. Annu Rev Immunol 7 339 369

56. McKenneyDWOnoderaHGormanLMimuraTRothsteinDM 1995 Distinct isoforms of the CD45 protein-tyrosine phosphatase differentially regulate interleukin 2 secretion and activation signal pathways involving Vav in T cells. J Biol Chem 270 24949 24954

57. KoretzkyGAPicusJThomasMLWeissA 1990 Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature 346 66 68

58. SchwinzerRSchravenBKyasUMeuerSCWonigeitK 1992 Phenotypical and biochemical characterization of a variant CD45R expression pattern in human leukocytes. Eur J Immunol 22 1095 1098

59. TerryLABrownMHBeverleyPC 1988 The monoclonal antibody, UCHL1, recognizes a 180,000 MW component of the human leucocyte-common antigen, CD45. Immunology 64 331 336

60. EarlLABaumLG 2008 CD45 glycosylation controls T-cell life and death. Immunol Cell Biol 86 608 615

61. YoungJLRamageJMGastonJSBeverleyPC 1997 In vitro responses of human CD45R0brightRA- and CD45R0-RAbright T cell subsets and their relationship to memory and naive T cells. Eur J Immunol 27 2383 2390

62. ThudeHHundrieserJWonigeitKSchwinzerR 1995 A point mutation in the human CD45 gene associated with defective splicing of exon A. Eur J Immunol 25 2101 2106

63. ZilchCFWalkerAMTimonMGoffLKWallaceDL 1998 A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans. Eur J Immunol 28 22 29

64. Smith-GarvinJEKoretzkyGAJordanMS 2009 T cell activation. Annu Rev Immunol 27 591 619

65. RazonableRR 2005 Epidemiology of cytomegalovirus disease in solid organ and hematopoietic stem cell transplant recipients. Am J Health Syst Pharm 62 S7 13

66. WindheimMBurgertHG 2002 Characterization of E3/49K, a novel, highly glycosylated E3 protein of the epidemic keratoconjunctivitis-causing adenovirus type 19a. J Virol 76 755 766

67. AntonssonAJohanssonPJ 2001 Binding of human and animal immunoglobulins to the IgG Fc receptor induced by human cytomegalovirus. J Gen Virol 82 1137 1145

68. MacCormacLPGrundyJE 1996 Human cytomegalovirus induces an Fc gamma receptor (Fc gammaR) in endothelial cells and fibroblasts that is distinct from the human cellular Fc gammaRs. J Infect Dis 174 1151 1161

69. VarkiACrockerPR 2009 I-type Lectins. VarkiACummingsRDEskoJDFreezeHHStanleyP Essentials of Glycobiology Cold Spring Harbor (NY) Cold Spring Harbor Laboratory Press 459 474

70. BaldwinTAOstergaardHL 2001 Developmentally regulated changes in glucosidase II association with, and carbohydrate content of, the protein tyrosine phosphatase CD45. J Immunol 167 3829 3835

71. UemuraKYokotaYKozutsumiYKawasakiT 1996 A unique CD45 glycoform recognized by the serum mannan-binding protein in immature thymocytes. J Biol Chem 271 4581 4584

72. RachmilewitzJBorovskyZRielyGJMillerRTykocinskiML 2003 Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45. J Biol Chem 278 14059 14065

73. StrausDBWeissA 1992 Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 70 585 593

74. HermistonMLXuZMajetiRWeissA 2002 Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. J Clin Invest 109 9 14

75. IlangumaranSArniSEchten-DeckertGBorischBHoessliDC 1999 Microdomain-dependent regulation of Lck and Fyn protein-tyrosine kinases in T lymphocyte plasma membranes. Mol Biol Cell 10 891 905

76. HarderTEngelhardtKR 2004 Membrane domains in lymphocytes - from lipid rafts to protein scaffolds. Traffic 5 265 275

77. FurukawaTItohMKruegerNXStreuliMSaitoH 1994 Specific interaction of the CD45 protein-tyrosine phosphatase with tyrosine-phosphorylated CD3 zeta chain. Proc Natl Acad Sci U S A 91 10928 10932

78. MustelinTWilliamsSTailorPCoutureCZennerG 1995 Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase. Eur J Immunol 25 942 946

79. FreibergBAKupferHMaslanikWDelliJKapplerJ 2002 Staging and resetting T cell activation in SMACs. Nat Immunol 3 911 917

80. ParikhKPoppemaSPeppelenboschMPVisserL 2009 Extracellular ligation-dependent CD45RB enzymatic activity negatively regulates lipid raft signal transduction. Blood 113 594 603

81. Ish-ShalomEGargirAAndreSBorovskyZOchanunaZ 2006 alpha2,6-Sialylation promotes binding of placental protein 14 via its Ca2+-dependent lectin activity: insights into differential effects on CD45RO and CD45RA T cells. Glycobiology 16 173 183

82. BilwesAMden HertogJHunterTNoelJP 1996 Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization. Nature 382 555 559

83. MajetiRXuZParslowTGOlsonJLDaikhDI 2000 An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103 1059 1070

84. DoHTBaarsWBornsKWindhagenASchwinzerR 2006 The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis. J Immunol 176 931 938

85. WindhagenASonmezDHornig-DoHTKalinowskyASchwinzerR 2007 Altered CD45 isoform expression in C77G carriers influences cytokine responsiveness and adhesion properties of T cells. Clin Exp Immunol 150 509 517

86. AmanoMGalvanMHeJBaumLG 2003 The ST6Gal I sialyltransferase selectively modifies N-glycans on CD45 to negatively regulate galectin-1-induced CD45 clustering, phosphatase modulation, and T cell death. J Biol Chem 278 7469 7475

87. DesaiDMSapJSchlessingerJWeissA 1993 Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase. Cell 73 541 554

88. BorstEMBenkartekCMesserleM 2007 Use of bacterial artificial chromosomes in generating targeted mutations in human and mouse cytomegaloviruses. Curr Protoc Immunol, Chapter 10 32.1 32.20

89. CheungTCHumphreysIRPotterKGNorrisPSShumwayHM 2005 Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc Natl Acad Sci U S A 102 13218 13223

90. BorstEMHahnGKoszinowskiUHMesserleM 1999 Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J Virol 73 8320 8329

91. ChaTATomEKembleGWDukeGMMocarskiES 1996 Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 70 78 83

92. HildingerMAbelKLOstertagWBaumC 1999 Design of 5′ untranslated sequences in retroviral vectors developed for medical use. J Virol 73 4083 4089

93. SchambachAMuellerDGallaMVerstegenMMWagemakerG 2006 Overcoming promoter competition in packaging cells improves production of self-inactivating retroviral vectors. Gene Ther 13 1524 1533

94. CossetFLTakeuchiYBattiniJLWeissRACollinsMK 1995 High-titer packaging cells producing recombinant retroviruses resistant to human serum. J Virol 69 7430 7436

95. OgilvySLouis-Dit-SullyCCooperJCassadyRLAlexanderDR 2003 Either of the CD45RB and CD45RO isoforms are effective in restoring T cell, but not B cell, development and function in CD45-null mice. J Immunol 171 1792 1800

96. WeissAStoboJD 1984 Requirement for the coexpression of T3 and the T cell antigen receptor on a malignant human T cell line. J Exp Med 160 1284 1299