1887

Abstract

Apart from classical antigen-presenting cells (APCs) like dendritic cells and macrophages, there are semiprofessional APCs such as endothelial cells (ECs) and Langerhans' cells. Human cytomegalovirus (HCMV) infects a wide range of cell types including the ECs which are involved in the trafficking and homing of T cells. By investigating the interaction of naïve T cells obtained from HCMV-seronegative umbilical cord blood with autologous HCMV-infected human umbilical vein ECs (HUVECs), we could show that the activation of naïve T cells occurred after 1 day of peripheral blood mononuclear cell (PBMC) exposure to HCMV-infected HUVECs. The percentage of activated T cells increased over time and the activation of naïve T cells was not induced by either autologous uninfected HUVECs or by autologous HCMV-infected fibroblasts. The activation of T cells occurred also when purified T cells were co-cultured with HCMV-infected HUVECs. In addition, in most of the donors only CD8 T cells were activated, when the purified T cells were exposed to HCMV-infected HUVECs. The activation of naïve T cells was inhibited when the NKG2D receptor was blocked on the surface of T cells and among the different NKG2D ligands, we identified two ligands (ULBP4 and MICA) on HCMV-infected HUVECs which might be the interaction partners of the NKG2D receptor. Using a functional cell culture assay, we could show that these activated naïve T cells specifically inhibited HCMV transmission. Altogether, we identified a novel specific activation mechanism of naïve T cells from the umbilical cord by HCMV-infected autologous HUVECs through interaction with NKG2D.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000976
2017-12-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/12/3068.html?itemId=/content/journal/jgv/10.1099/jgv.0.000976&mimeType=html&fmt=ahah

References

  1. McGoldrick SM, Bleakley ME, Guerrero A, Turtle CJ, Yamamoto TN et al. Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo . Blood 2013; 121:2796–2803 [View Article][PubMed]
    [Google Scholar]
  2. Rocha V, Gluckman E. Eurocord and European Blood and Marrow Transplant Group Clinical use of umbilical cord blood hematopoietic stem cells. Biol Blood Marrow Transplant 2006; 12:34–41 [View Article][PubMed]
    [Google Scholar]
  3. Butler MG, Menitove JE. Umbilical cord blood banking: an update. J Assist Reprod Genet 2011; 28:669–676 [View Article][PubMed]
    [Google Scholar]
  4. Hashem H, Lazarus HM. Double umbilical cord blood transplantation: relevance of persistent mixed-unit chimerism. Biol Blood Marrow Transplant 2015; 21:612–619 [View Article][PubMed]
    [Google Scholar]
  5. Mulanovich VE, Jiang Y, de Lima M, Shpall EJ, Champlin RE et al. Infectious complications in cord blood and T-cell depleted haploidentical stem cell transplantation. Am J Blood Res 2011; 1:98[PubMed]
    [Google Scholar]
  6. Cahu X, Rialland F, Touzeau C, Chevallier P, Guillaume T et al. Infectious complications after unrelated umbilical cord blood transplantation in adult patients with hematologic malignancies. Biol Blood Marrow Transplant 2009; 15:1531–1537 [View Article][PubMed]
    [Google Scholar]
  7. Al-Hajjar S, Al Seraihi A, Al Muhsen S, Ayas M, Al Jumaah S et al. Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes. Hematol Oncol Stem Cell Ther 2011; 4:67–72 [View Article][PubMed]
    [Google Scholar]
  8. Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000; 13:83–121 [View Article][PubMed]
    [Google Scholar]
  9. Albano MS, Taylor P, Pass RF, Scaradavou A, Ciubotariu R et al. Umbilical cord blood transplantation and cytomegalovirus: posttransplantation infection and donor screening. Blood 2006; 108:4275–4282 [View Article][PubMed]
    [Google Scholar]
  10. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother 2013; 45:260 [View Article][PubMed]
    [Google Scholar]
  11. Schleiss MR. Cytomegalovirus in the neonate: immune correlates of infection and protection. Clin Dev Immunol 2013; 2013:1–14 [View Article][PubMed]
    [Google Scholar]
  12. Cheeran MC, Lokensgard JR, Schleiss MR. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 2009; 22:99–126 [View Article][PubMed]
    [Google Scholar]
  13. Nassetta L, Kimberlin D, Whitley R. Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies. J Antimicrob Chemother 2009; 63:862–867 [View Article][PubMed]
    [Google Scholar]
  14. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection. Pediatr Clin North Am 2013; 60:335–349 [View Article]
    [Google Scholar]
  15. Harris DT, Schumacher MJ, Locascio J, Besencon FJ, Olson GB et al. Phenotypic and functional immaturity of human umbilical cord blood T lymphocytes. Proc Natl Acad Sci USA 1992; 89:10006–10010 [View Article][PubMed]
    [Google Scholar]
  16. Zola H, Fusco M, Weedon H, Macardle PJ, Ridings J et al. Reduced expression of the interleukin-2-receptor gamma chain on cord blood lymphocytes: relationship to functional immaturity of the neonatal immune response. Immunology 1996; 87:86[PubMed]
    [Google Scholar]
  17. Gibbons D, Fleming P, Virasami A, Michel ML, Sebire NJ et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat Med 2014; 20:1206–1210 [View Article][PubMed]
    [Google Scholar]
  18. Nitsche A, Zhang M, Clauss T, Siegert W, Brune K et al. Cytokine profiles of cord and adult blood leukocytes: differences in expression are due to differences in expression and activation of transcription factors. BMC Immunol 2007; 8:18 [View Article][PubMed]
    [Google Scholar]
  19. Chalmers IM, Janossy G, Contreras M, Navarrete C. Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 1998; 92:11–18[PubMed]
    [Google Scholar]
  20. Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 2007; 7:543–555 [View Article][PubMed]
    [Google Scholar]
  21. Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 2008; 181:5829–5835 [View Article][PubMed]
    [Google Scholar]
  22. Rodríguez-Pinto D. B cells as antigen presenting cells. Cell Immunol 2005; 238:67–75 [View Article][PubMed]
    [Google Scholar]
  23. Sundstrom JB, Ansari AA. Comparative study of the role of professional versus semiprofessional or nonprofessional antigen presenting cells in the rejection of vascularized organ allografts. Transpl Immunol 1995; 3:273–289 [View Article][PubMed]
    [Google Scholar]
  24. Mai J, Virtue A, Shen J, Wang H, Yang X-F. An evolving new paradigm: endothelial cells – conditional innate immune cells. J Hematol Oncol 2013; 6:61 [View Article]
    [Google Scholar]
  25. Bell E. Innate immunity: Endothelial cells as sentinels. Nat Rev Immunol 2009; 9:532–533 [View Article]
    [Google Scholar]
  26. Razakandrainibe R, Pelleau S, Grau GE, Jambou R. Antigen presentation by endothelial cells: what role in the pathophysiology of malaria?. Trends Parasitol 2012; 28:151–160 [View Article][PubMed]
    [Google Scholar]
  27. Lohse AW, Knolle PA, Bilo K, Uhrig A, Waldmann C et al. Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenterology 1996; 110:1175–1181 [View Article][PubMed]
    [Google Scholar]
  28. Nolz JC, Starbeck-Miller GR, Harty JT. Naive, effector and memory CD8 T-cell trafficking: parallels and distinctions. Immunotherapy 2011; 3:1223–1233 [View Article][PubMed]
    [Google Scholar]
  29. Lewis M, Tarlton JF, Cose S. Memory versus naive T-cell migration. Immunol Cell Biol 2008; 86:226–231 [View Article][PubMed]
    [Google Scholar]
  30. Marelli-Berg FM, Jarmin SJ. Antigen presentation by the endothelium: a green light for antigen-specific T cell trafficking?. Immunol Lett 2004; 93:109–113 [View Article][PubMed]
    [Google Scholar]
  31. Böttcher JP, Schanz O, Wohlleber D, Abdullah Z, Debey-Pascher S et al. Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity. Cell Rep 2013; 3:779–795 [View Article][PubMed]
    [Google Scholar]
  32. Kern M, Popov A, Scholz K, Schumak B, Djandji D et al. Virally infected mouse liver endothelial cells trigger CD8+ T-cell immunity. Gastroenterology 2010; 138:336–346 [View Article][PubMed]
    [Google Scholar]
  33. Schurich A, Böttcher JP, Burgdorf S, Penzler P, Hegenbarth S et al. Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells. Hepatology 2009; 50:909–919 [View Article][PubMed]
    [Google Scholar]
  34. Danese S, Dejana E, Fiocchi C. Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol 2007; 178:6017–6022 [View Article][PubMed]
    [Google Scholar]
  35. Carman CV, Martinelli R. T Lymphocyte-endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front Immunol 2015; 6:603 [View Article][PubMed]
    [Google Scholar]
  36. Gerna G, Sarasini A, Patrone M, Percivalle E, Fiorina L et al. Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. J Gen Virol 2008; 89:853–865 [View Article][PubMed]
    [Google Scholar]
  37. Sinzger C. Entry route of HCMV into endothelial cells. J Clin Virol 2008; 41:174–179 [View Article][PubMed]
    [Google Scholar]
  38. Simms PE, Ellis TM. Utility of flow cytometric detection of CD69 expression as a rapid method for determining poly- and oligoclonal lymphocyte activation. Clin Diagn Lab Immunol 1996; 3:301–304[PubMed]
    [Google Scholar]
  39. Radulovic K, Rossini V, Manta C, Holzmann K, Kestler HA et al. The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine. PLoS One 2013; 8:e65413 [View Article][PubMed]
    [Google Scholar]
  40. Vieira Braga FA, Hertoghs KM, van Lier RA, van Gisbergen KP. Molecular characterization of HCMV-specific immune responses: parallels between CD8+ T cells, CD4+ T cells, and NK cells. Eur J Immunol 2015; 45:2433–2445 [View Article][PubMed]
    [Google Scholar]
  41. Lilleri D, Fornara C, Revello MG, Gerna G. Human cytomegalovirus-specific memory CD8+ and CD4+ T cell differentiation after primary infection. J Infect Dis 2008; 198:536–543 [View Article][PubMed]
    [Google Scholar]
  42. Park J, Han K. Single-color multitarget flow cytometry using monoclonal antibodies labeled with different intensities of the same fluorochrome. Ann Lab Med 2012; 32:171 [View Article][PubMed]
    [Google Scholar]
  43. Subramanian N, Wu Z, Mertens TM. Phenotypic characterization of human cytomegalovirus strains in cell cultures based on their transmission kinetics. J Gen Virol 2016; 97:2376–2386 [View Article][PubMed]
    [Google Scholar]
  44. Sukdolak C, Tischer S, Dieks D, Figueiredo C, Goudeva L et al. CMV-, EBV- and ADV-specific T cell immunity: screening and monitoring of potential third-party donors to improve post-transplantation outcome. Biol Blood Marrow Transplant 2013; 19:1480–1492 [View Article][PubMed]
    [Google Scholar]
  45. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004; 103:3065–3072 [View Article]
    [Google Scholar]
  46. Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J Gen Virol 2006; 87:1763–1779 [View Article][PubMed]
    [Google Scholar]
  47. Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res 2011; 157:151–160 [View Article][PubMed]
    [Google Scholar]
  48. Klenerman P, Oxenius A. T cell responses to cytomegalovirus. Nat Rev Immunol 2016; 16:367–377 [View Article][PubMed]
    [Google Scholar]
  49. Jackson SE, Sedikides GX, Mason GM, Okecha G, Wills MR et al. Human cytomegalovirus (HCMV)-specific CD4+ T cells are polyfunctional and can respond to HCMV-infected dendritic cells in vitro . J Virol 2017; 91:e02128-16 [View Article][PubMed]
    [Google Scholar]
  50. Gamadia LE, Rentenaar RJ, van Lier RA, Ten Berge IJ. Properties of CD4+ T cells in human cytomegalovirus infection. Hum Immunol 2004; 65:486–492 [View Article][PubMed]
    [Google Scholar]
  51. Wallace DL, Masters JE, de Lara CM, Henson SM, Worth A et al. Human cytomegalovirus-specific CD8+ T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects: Lifespan and function of HCMV-specific CD8 expansions. Immunology 2011; 132:27–38 [Crossref]
    [Google Scholar]
  52. Vaz-Santiago J, Lulé J, Rohrlich P, Jacquier C, Gibert N et al. Ex vivo stimulation and expansion of both CD4+ and CD8+ T cells from peripheral blood mononuclear cells of human cytomegalovirus-seropositive blood donors by using a soluble recombinant chimeric protein, IE1-pp65. J Virol 2001; 75:7840–7847 [View Article][PubMed]
    [Google Scholar]
  53. Dunn HS, Haney DJ, Ghanekar SA, Stepick-Biek P, Lewis DB et al. Dynamics of CD4 and CD8 T cell responses to cytomegalovirus in healthy human donors. J Infect Dis 2002; 186:15–22 [View Article][PubMed]
    [Google Scholar]
  54. Shulman Z, Cohen SJ, Roediger B, Kalchenko V, Jain R et al. Transendothelial migration of lymphocytes mediated by intraendothelial vesicle stores rather than by extracellular chemokine depots. Nat Immunol 2011; 13:67–76 [View Article][PubMed]
    [Google Scholar]
  55. Park HJ, Zhang Y, Georgescu SP, Johnson KL, Kong D et al. Human umbilical vein endothelial cells and human dermal microvascular endothelial cells offer new insights into the relationship between lipid metabolism and angiogenesis. Stem Cell Rev 2006; 2:93–101 [View Article][PubMed]
    [Google Scholar]
  56. Hirosue S, Vokali E, Raghavan VR, Rincon-Restrepo M, Lund AW et al. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J Immunol 2014; 192:5002–5011 [View Article][PubMed]
    [Google Scholar]
  57. Chen XL, Xia ZF, Wei D, Liao HG, Ben DF et al. Expression and regulation of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells induced by sera from severely burned patients. Crit Care Med 2004; 32:77–82 [View Article][PubMed]
    [Google Scholar]
  58. O'Brien PJ, Prevost N, Molino M, Hollinger MK, Woolkalis MJ et al. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J Biol Chem 2000; 275:13502–13509[PubMed] [Crossref]
    [Google Scholar]
  59. Raab M, Daxecker H, Markovic S, Karimi A, Griesmacher A et al. Variation of adhesion molecule expression on human umbilical vein endothelial cells upon multiple cytokine application. Clin Chim Acta 2002; 321:11–16 [View Article][PubMed]
    [Google Scholar]
  60. Walker JD, Maier CL, Pober JS. Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes. J Immunol 2009; 182:1548–1559 [View Article][PubMed]
    [Google Scholar]
  61. Kelley JL, Rozek MM, Suenram CA, Schwartz CJ. Activation of human blood monocytes by adherence to tissue culture plastic surfaces. Exp Mol Pathol 1987; 46:266–278 [View Article][PubMed]
    [Google Scholar]
  62. Abbas AK, Lichtman AH, Pillai S, Baker DL. CYTOKINES. In Cellular Molecular Immunology Elsevier; 2010 pp. 267–301 [Crossref]
    [Google Scholar]
  63. Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunol Res 2015; 3:575–582 [View Article][PubMed]
    [Google Scholar]
  64. Björkström NK, Béziat V, Cichocki F, Liu LL, Levine J et al. CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells. Blood 2012; 120:3455–3465 [View Article][PubMed]
    [Google Scholar]
  65. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2001; 2:255–260 [View Article][PubMed]
    [Google Scholar]
  66. Tomić A, Varanasi PR, Golemac M, Malić S, Riese P et al. Activation of innate and adaptive immunity by a recombinant human cytomegalovirus strain expressing an NKG2D ligand. PLoS Pathog 2016; 12:e1006015 [View Article][PubMed]
    [Google Scholar]
  67. Spear P, Wu MR, Sentman ML, Sentman CL. NKG2D ligands as therapeutic targets. Cancer Immun 2013; 13:8[PubMed]
    [Google Scholar]
  68. Champsaur M, Lanier LL. Effect of NKG2D ligand expression on host immune responses: Immune response to NKG2D ligands. Immunol Rev 2010; 235:267–285 [Crossref]
    [Google Scholar]
  69. Lodoen MB, Lanier LL. Viral modulation of NK cell immunity. Nat Rev Microbiol 2005; 3:59–69 [View Article][PubMed]
    [Google Scholar]
  70. Dunn C, Chalupny NJ, Sutherland CL, Dosch S, Sivakumar PV et al. Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. J Exp Med 2003; 197:1427–1439 [View Article][PubMed]
    [Google Scholar]
  71. Müller S, Zocher G, Steinle A, Stehle T. Structure of the HCMV UL16-MICB complex elucidates select binding of a viral immunoevasin to diverse NKG2D ligands. PLoS Pathog 2010; 6:e1000723 [View Article][PubMed]
    [Google Scholar]
  72. Bennett NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G et al. Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus. J Immunol 2010; 185:1093–1102 [View Article][PubMed]
    [Google Scholar]
  73. Chalupny NJ, Rein-Weston A, Dosch S, Cosman D. Down-regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142. Biochem Biophys Res Commun 2006; 346:175–181 [View Article][PubMed]
    [Google Scholar]
  74. Fielding CA, Aicheler R, Stanton RJ, Wang EC, Han S et al. Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. PLoS Pathog 2014; 10:e1004058 [View Article][PubMed]
    [Google Scholar]
  75. Bayer C, Varani S, Wang L, Walther P, Zhou S et al. Human cytomegalovirus infection of M1 and M2 macrophages triggers inflammation and autologous T-cell proliferation. J Virol 2013; 87:67–79 [View Article][PubMed]
    [Google Scholar]
  76. Wu Z, Sinzger C, Frascaroli G, Reichel J, Bayer C et al. Human cytomegalovirus-induced NKG2Chi CD57hi natural killer cells are effectors dependent on humoral antiviral immunity. J Virol 2013; 87:7717–7725 [View Article][PubMed]
    [Google Scholar]
  77. Azandeh S, Orazizadeh M, Hashemitabar M, Khodadadi A, Shayesteh AA et al. Mixed enzymatic-explant protocol for isolation of mesenchymal stem cells from Wharton’s jelly and encapsulation in 3D culture system. J Biomed Sci Eng 2012; 5:580–586 [View Article]
    [Google Scholar]
  78. El-Nawasany MA, Khedr EG, Motawee ME, Ali ZA, Kamel HE et al. Culture and identification of undifferentiated Wharton’s Jelly mesenchymal stem cells (WJ-MSCs) derived from the human umbilical cord. Open Sci J Clin Med 2015; 3:182–187
    [Google Scholar]
  79. Tischer BK, Smith GA, Osterrieder N. En passant mutagenesis: a two step markerless red recombination system. In Braman J. (editor) In Vitro Mutagenesis Protocols vol. 634 Totowa, NJ: Humana Press; 2010 pp. 421–430 [Crossref]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000976
Loading
/content/journal/jgv/10.1099/jgv.0.000976
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error