Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pediatric Transplants

Cellular immune parameters associated with spontaneous control of CMV in children who underwent transplantation

Abstract

CD4+ T-cell functions that best correlate with CMV control were evaluated by studying the relationship between CMV infection and CMV-specific immune recovery as determined by proliferation assay and intracytoplasmic-IFNγ assay. A total of 30 children (mean age: 8.30 years) who received an allogeneic hematopoietic SCT (HSCT) were included. In total, 13 recipients were seronegative before HSCT. None developed CMV infection or CMV-specific immunity. A total of 17 recipients were seropositive: (i) four patients spontaneously controlled CMV. The median of CMV-specific IFNγ-secreting CD4 T cells was 9.13/μl at month 3 in these four patients and three of the four patients evidenced optimal proliferative responses since month 1; (ii) in 10 patients who received anti-CMV chemotherapy because of prolonged viremia, lower (P=0.016) IFNγ responses (0.39/μl), together with delayed and/or depressed proliferative responses, were observed; (iii) finally, one patient with early CMV-associated disease had undetectable proliferative and IFNγ responses until month 3. In conclusion, both intense IFNγ responses and early proliferative responses seem to be associated with optimal CMV control.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev G et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8T cells. J Exp Med 2005; 201: 1031–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gratama JW, van Esser JW, Lamers CH, Tournay C, Lowenberg B, Bolhuis RL et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood 2001; 98: 1358–1364.

    Article  CAS  PubMed  Google Scholar 

  3. Reusser P, Cathomas G, Attenhofer R, Tamm M, Thiel G . Cytomegalovirus (CMV)-specific T cell immunity after renal transplantation mediates protection from CMV disease by limiting the systemic virus load. J Infect Dis 1999; 180: 247–253.

    Article  CAS  PubMed  Google Scholar 

  4. Sacre K, Carcelain G, Cassoux N, Fillet AM, Costagliola D, Vittecoq D et al. Repertoire, diversity, and differentiation of specific CD8T cells are associated with immune protection against human cytomegalovirus disease. J Exp Med 2005; 201: 1999–2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen SF, Tu WW, Sharp MA, Tongson EC, He XS, Greenberg HB et al. Antiviral CD8T cells in the control of primary human cytomegalovirus infection in early childhood. J Infect Dis 2004; 189: 1619–1627.

    Article  PubMed  Google Scholar 

  6. Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ . Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 2003; 101: 2686–2692.

    Article  CAS  PubMed  Google Scholar 

  7. Hebart H, Daginik S, Stevanovic S, Grigoleit U, Dobler A, Baur M et al. Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation. Blood 2002; 99: 3830–3837.

    Article  CAS  PubMed  Google Scholar 

  8. Foster AE, Gottlieb DJ, Sartor M, Hertzberg MS, Bradstock KF . Cytomegalovirus-specific CD4+ and CD8+ T-cells follow a similar reconstitution pattern after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 501–511.

    Article  PubMed  Google Scholar 

  9. Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 2003; 101: 407–414.

    Article  CAS  PubMed  Google Scholar 

  10. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333: 1038–1044.

    Article  CAS  PubMed  Google Scholar 

  11. Harari A, Vallelian F, Meylan PR, Pantaleo G . Functional heterogeneity of memory CD4T cell responses in different conditions of antigen exposure and persistence. J Immunol 2005; 174: 1037–1045.

    Article  CAS  PubMed  Google Scholar 

  12. Boaz MJ, Waters A, Murad S, Easterbrook PJ, Vyakarnam A . Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4T cell responses is associated with nonprogression in HIV-1 infection. J Immunol 2002; 169: 6376–6385.

    Article  CAS  PubMed  Google Scholar 

  13. Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 2007; 13: 843–850.

    Article  CAS  PubMed  Google Scholar 

  14. Emu B, Sinclair E, Favre D, Moretto WJ, Hsue P, Hoh R et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol 2005; 79: 14169–14178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP et al. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 2003; 198: 1909–1922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Millington KA, Innes JA, Hackforth S, Hinks TS, Deeks JJ, Dosanjh DP et al. Dynamic relationship between IFN-gamma and IL-2 profile of Mycobacterium tuberculosis-specific T cells and antigen load. J Immunol 2007; 178: 5217–5226.

    Article  CAS  PubMed  Google Scholar 

  17. Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 2003; 102: 3060–3067.

    Article  CAS  PubMed  Google Scholar 

  18. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR . Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979.

    CAS  PubMed  Google Scholar 

  19. Ljungman P, Griffiths P, Paya C . Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34: 1094–1097.

    Article  PubMed  Google Scholar 

  20. Sester M, Sester U, Gartner B, Heine G, Girndt M, Mueller-Lantzsch N et al. Levels of virus-specific CD4T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation 2001; 71: 1287–1294.

    Article  CAS  PubMed  Google Scholar 

  21. Zaunders JJ, Dyer WB, Munier ML, Ip S, Liu J, Amyes E et al. CD127+CCR5+CD38+++ CD4+ Th1 effector cells are an early component of the primary immune response to vaccinia virus and precede development of interleukin-2+ memory CD4+ T cells. J Virol 2006; 80: 10151–10161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lilleri D, Gerna G, Fornara C, Lozza L, Maccario R, Locatelli F . Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants. Blood 2006; 108: 1406–1412.

    Article  CAS  PubMed  Google Scholar 

  23. Pourgheysari B, Piper KP, McLarnon A, Arrazi J, Bruton R, Clark F et al. Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant 2009; 43: 853–861.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the clinical team for patient care, Guylaine Boiry, Anne-Marie Courchinoux, Elodie Geneletti and Ingrid Hamon for excellent technical assistance and Céline Neto for typing the manuscript and drawing the figures. This work was supported by Assistance Publique—Hôpitaux de Paris and University Paris VII, France.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G Sterkers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guérin, V., Dalle, JH., Pédron, B. et al. Cellular immune parameters associated with spontaneous control of CMV in children who underwent transplantation. Bone Marrow Transplant 45, 442–449 (2010). https://doi.org/10.1038/bmt.2009.179

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.179

Keywords

This article is cited by

Search

Quick links