1887

Journal of General Virology header logo

Volume 97, Issue 8

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients Free

Abstract

Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (=40) and immunocompromised transplant patients (=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-γ) CD4 and CD8 T-cells. Circulating CXCR5 CD4 (memory T follicular helper – T-cells) were identified as activated T (ICOSPD-1CCR7) and quiescent cells. In the early stages of primary infection, activated T cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4 T-cells, HCMV clearance and progressive reduction in activated T cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated T cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated T cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of T cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibody response , human cytomegalovirus , immunocompetent , immunocompromised patient , primary HCMV infection and TFHcells
© 2016 The Authors

Erratum

An erratum has been published for this content:
Corrigendum to Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000488
2016-08-01
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/8/1928.html?itemId=/content/journal/jgv/10.1099/jgv.0.000488&mimeType=html&fmt=ahah

References

  1. Bentebibel S.-E., Lopez S., Obermoser G., Schmitt N., Mueller C., Harrod C., Flano E., Mejias A., Albrecht R. A. et al. 2013; Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med 5:ra132 [View Article]
     [Google Scholar]
  2. Boswell K. L., Paris R., Boritz E., Ambrozak D., Yamamoto T., Darko S., Wloka K., Wheatley A., Narpala S. et al. 2014; Loss of circulating CD4 T cells with B cell helper function during chronic HIV infection. PLoS Pathog 10:e1003853 [View Article][PubMed]
     [Google Scholar]
  3. Breitfeld D., Ohl L., Kremmer E., Ellwart J., Sallusto F., Lipp M., Förster R. 2000; Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 192:1545–1552[PubMed] [CrossRef]
     [Google Scholar]
  4. Butler N. S., Kulu D. I 2015; The regulation of T follicular helper responses during infection. Curr Opin in Immunol 34:68–74 [CrossRef]
     [Google Scholar]
  5. Chevalier N., Jarrossay D., Ho E., Avery D. T., Ma C. S., Yu D., Sallusto F., Tangye S. G., Mackay C. R. 2011; CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J Immunol 186:5556–5568 [View Article][PubMed]
     [Google Scholar]
  6. Crotty S. 2014; T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529–542 [View Article][PubMed]
     [Google Scholar]
  7. Cubas R. A., Mudd J. C., Savoye A. L., Perreau M., van Grevenynghe J., Metcalf T., Connick E., Meditz A., Freeman G. J. et al. 2013; Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 19:494–499 [View Article][PubMed]
     [Google Scholar]
  8. Förster R., Emrich T., Kremmer E., Lipp M. 1994; Expression of the G-protein-coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood 84:830–840[PubMed]
     [Google Scholar]
  9. Furione M., Rognoni V., Cabano E., Baldanti F. 2012; Kinetics of human cytomegalovirus (HCMV) DNAemia in transplanted patients expressed in international units as determined with the Abbott RealTime CMV assay and an in-house assay. J Clin Virol 55:317–322 [View Article][PubMed]
     [Google Scholar]
  10. Furione M., Rognoni V., Sarasini A., Zavattoni M., Lilleri D., Gerna G., Revello M. G. 2013; Slow increase in IgG avidity correlates with prevention of human cytomegalovirus transmission to the fetus. J Med Virol 85:1960–1967 [View Article][PubMed]
     [Google Scholar]
  11. Gabanti E., Bruno F., Lilleri D., Fornara C., Zelini P., Cane I., Migotto C., Sarchi E., Furione M. et al. 2014; Human cytomegalovirus (HCMV)-specific memory CD4+ and CD8+ T cells are both required for prevention of HCMV disease in seropositive solid-organ transplant recipients. PLoS One 9:e106044 [View Article]
     [Google Scholar]
  12. Geiger R., Duhen T., Lanzavecchia A., Sallusto F. 2009; Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J Exp Med 206:1525–1534 [View Article][PubMed]
     [Google Scholar]
  13. Gerna G., Baldanti F., Torsellini M., Minoli L., Viganò M., Oggionnis T., Rampino T., Castiglioni B., Goglio A. et al. 2007; Evaluation of cytomegalovirus DNAaemia versus pp65- antigenaemia cutoff for guiding preemptive therapy in transplant recipients: a randomized study. Antivir Ther 12:63–72[PubMed]
     [Google Scholar]
  14. Gerna G., Sarasini A., Patrone M., Percivalle E., Fiorina L., Campanini G., Gallina A., Baldanti F., Revello M. G. 2008; Human cytomegalovirus serum neutralizing antibodies block virus infection of endothelial/epithelial cells, but not fibroblasts, early during primary infection. J Gen Virol 89:853–865 [View Article][PubMed]
     [Google Scholar]
  15. Gerna G., Lilleri D., Chiesa A., Zelini P., Furione M., Comolli G., Pellegrini C., Sarchi E., Migotto C. et al. 2011; Virologic and immunologic monitoring of cytomegalovirus to guide preemptive therapy in solid-organ transplantation. Am J Transplant 11:2463–2471 [View Article][PubMed]
     [Google Scholar]
  16. Gerna G., Lilleri D., Fornara C., Bruno F., Gabanti E., Cane I., Furione M., Revello M. G., Fornara C., Bruno C. 2015; Differential kinetics of human cytomegalovirus load and antibody responses in primary infection of the immunocompetent and immunocompromised host. J Gen Virol 96:360–369 [View Article][PubMed]
     [Google Scholar]
  17. He J., Tsai L. M., Leong Y. A., Hu X., Ma C. S., Chevalier N., Sun X., Vandenberg K., Rockman S. et al. 2013; Circulating precursor CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 39:770–781 [View Article][PubMed]
     [Google Scholar]
  18. Kabanova A., Perez L., Lilleri D., Marcandalli J., Agatic G., Becattini S., Preite S., Fuschillo D., Percivalle E. et al. 2014; Antibody-driven design of a human cytomegalovirus gHgLpUL128L subunit vaccine that selectively elicits potent neutralizing antibodies. Proc Natl Acad Sci U S A 111:17965–17970 [View Article][PubMed]
     [Google Scholar]
  19. Kim C. H., Rott L. S., Clark-Lewis I., Campbell D. J., Wu L., Butcher E. C. 2001; Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J Exp Med 193:1373–1381[PubMed] [CrossRef]
     [Google Scholar]
  20. Leddon S. A., Richards K. A., Treanor J. J., Sant A. J. 2015; Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults. Immunology 146:157–162 [View Article][PubMed]
     [Google Scholar]
  21. Lilleri D., Baldanti F., Gatti M., Rovida F., Dossena L., De Grazia S., Torsellini M., Gerna G. 2004; Clinically-based determination of safe DNAemia cutoff levels for preemptive therapy of human cytomegalovirus infections in solid organ and hematopoietic stem cell transplant recipients. J Med Virol 73:412–418 [View Article][PubMed]
     [Google Scholar]
  22. Lilleri D., Kabanova A., Lanzavecchia A., Gerna G. 2012; Antibodies against neutralization epitopes of human cytomegalovirus gH/gL/pUL128-130-131 complex and virus spreading may correlate with virus control in vivo. J Clin Immunol 32:1324–1331 [View Article][PubMed]
     [Google Scholar]
  23. Lilleri D., Kabanova A., Revello M. G., Percivalle E., Sarasini A., Genini E., Sallusto F., Lanzavecchia A., Corti D. et al. 2013; Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH/gL/pUL128-130-131 complex during primary infection. PLoS One 8:e59863 [View Article][PubMed]
     [Google Scholar]
  24. Lindqvist M., van Lunzen J., Soghoian D. Z., Kuhl B. D., Ranasinghe S., Kranias G., Flanders M. D., Cutler S., Yudanin N. et al. 2012; Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest 122:3271–3280 [View Article][PubMed]
     [Google Scholar]
  25. Locci M., Havenar-Daughton C., Landais E., Wu J., Kroenke M. A., Arlehamn C. L., Su L. F., Cubas R., Davis M. M. et al. 2013; Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 39:758–769 [View Article][PubMed]
     [Google Scholar]
  26. Lozza L., Lilleri D., Percivalle E., Fornara C., Comolli G., Revello M. G., Gerna G. 2005; Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells. Eur J Immunol 35:1795–1804 [View Article][PubMed]
     [Google Scholar]
  27. Morita R., Schmitt N., Bentebibel S. E., Ranganathan R., Bourdery L., Zurawski G., Foucat E., Dullaers M., Oh S. et al. 2011; Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34:108–121 [View Article][PubMed]
     [Google Scholar]
  28. Perreau M., Savoye A. L., De Crignis E., Corpataux J. M., Cubas R., Haddad E. K., De Leval L., Graziosi C., Pantaleo G. 2013; Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med 210:143–156 [View Article][PubMed]
     [Google Scholar]
  29. Recher M., Lang K. S., Hunziker L., Freigang S., Eschli B., Harris N. L., Navarini A., Senn B. M., Fink K. et al. 2004; Deliberate removal of T cell help improves virus-neutralizing antibody production. Nat Immunol 5:934–942 [View Article][PubMed]
     [Google Scholar]
  30. Revello M. G., Genini E., Gorini G., Klersy C., Piralla A., Gerna G. 2010; Comparative evaluation of eight commercial human cytomegalovirus IgG avidity assays. J Clin Virol 48:255–259 [View Article][PubMed]
     [Google Scholar]
  31. Revello M. G., Fabbri E., Furione M., Zavattoni M., Lilleri D., Tassis B., Quarenghi A., Cena C., Arossa A. et al. 2011; Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience. J Clin Virol 50:303–307 [View Article][PubMed]
     [Google Scholar]
  32. Sage P. T., Alvarez D., Godec J., von Andrian U. H., Sharpe A. H. 2014; Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest 124:5191–5204 [View Article][PubMed]
     [Google Scholar]
  33. Schaerli P., Willimann K., Lang A. B., Lipp M., Loetscher P., Moser B. 2000; CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192:1553–1562[PubMed] [CrossRef]
     [Google Scholar]
  34. Schmitt N., Bentebibel S. E., Ueno H. 2014; Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 35:436–442 [View Article][PubMed]
     [Google Scholar]
  35. Schultz B. T., Teigler J. E., Pissani F., Oster A. F., Kranias G., Alter G., Marovich M., Eller M. A., Dittmer U. et al. 2016; Circulating HIV-specific interleukin-21+ CD4+ T cells represent peripheral Tfh cells with antigen-dependent helper functions. Immunity 44:167–178 [View Article][PubMed]
     [Google Scholar]
  36. Ueno H., Banchereau J., Vinuesa C. G. 2015; Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142–152 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000488
Loading
Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients
J. Gen. Virol. 97, 1928 (2016); https://doi.org/10.1099/jgv.0.000488
/content/journal/jgv/10.1099/jgv.0.000488
/content/journal/jgv/10.1099/jgv.0.000488
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited Most Cited RSS feed

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