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:

Mesenchymal stromal cells inhibit proliferation of virus-specific CD8+ T cells

Leukemia volume 28, pages 2388–2394 (2014)Cite this article

Subjects

Abstract

Mesenchymal stromal cells (MSCs) possess broad immunomodulatory capacities that are currently investigated for potential clinical application in treating autoimmune disorders. Third-party MSCs suppress alloantigen-induced proliferation of peripheral blood mononuclear cells providing the rationale for clinical use in graft-versus-host disease (GvHD). We confirmed that MSCs strongly inhibited proliferation of CD8+ T cells in a mixed lymphocyte reaction. However, MSCs also suppressed proliferation of T cells specifically recognizing cytomegalovirus (CMV) and influenza virus. Inhibition was dose dependent, but independent of the culture medium. MSCs inhibited proliferation of specific CD8+ T cells and the release of IFN-γ by specific CD8+ T cells for immunodominant HLA-A2- and HLA-B7- restricted antigen epitopes derived from CMV phosphoprotein 65 and influenza matrix protein. This is in contrast to a recently reported scenario where MSCs exert differential effects on alloantigen and virus-specific T cells potentially having an impact on surveillance and prophylaxis of patients treated by MSCs.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 1974; 2: 83–92.

    CAS  PubMed  Google Scholar 

  2. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  3. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  Google Scholar 

  4. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC . Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389–397.

    Article  CAS  Google Scholar 

  5. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.

    Article  CAS  Google Scholar 

  6. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439–1441.

    Article  Google Scholar 

  7. Galipeau J . The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 2013; 15: 2–8.

    Article  Google Scholar 

  8. Abdelrazik H, Spaggiari GM, Chiossone L, Moretta L . Mesenchymal stem cells expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell proliferation and function. Eur J Immunol 2011; 41: 3281–3290.

    Article  CAS  Google Scholar 

  9. Doucet C, Ernou I, Zhang Y, Llense JR, Begot L, Holy X et al. Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. J Cell Physiol 2005; 205: 228–236.

    Article  CAS  Google Scholar 

  10. Bernardo ME, Avanzini MA, Perotti C, Cometa AM, Moretta A, Lenta E et al. Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. J Cell Physiol 2007; 211: 121–130.

    Article  CAS  Google Scholar 

  11. Perez-Ilzarbe M, Diez-Campelo M, Aranda P, Tabera S, Lopez T, del Canizo C et al. Comparison of ex vivo expansion culture conditions of mesenchymal stem cells for human cell therapy. Transfusion 2009; 49: 1901–1910.

    Article  CAS  Google Scholar 

  12. Ludwig A, Saffrich R, Eckstein V, Bruckner T, Wagner W, Ho AD et al. Functional potentials of human hematopoietic progenitor cells are maintained by mesenchymal stromal cells and not impaired by plerixafor. Cytotherapy 2014; 16: 111–121.

    Article  CAS  Google Scholar 

  13. Jin N, Malcherek G, Mani J, Zurleit R, Schmitt A, Chen B et al. Suppression of cytomegalovirus-specific CD8+ T cells by everolimus. Leuk Lymphoma 2014; 55: 1144–1150.

    Article  CAS  Google Scholar 

  14. Karlsson H, Samarasinghe S, Ball LM, Sundberg B, Lankester AC, Dazzi F et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 2008; 112: 532–541.

    Article  CAS  Google Scholar 

  15. Sundin M, Orvell C, Rasmusson I, Sundberg B, Ringden O, Le Blanc K . Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Marrow Transplant 2006; 37: 1051–1059.

    Article  CAS  Google Scholar 

  16. Rasmusson I, Uhlin M, Le Blanc K, Levitsky V . Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes. J Leukoc Biol 2007; 82: 887–893.

    Article  CAS  Google Scholar 

  17. Rasmusson I, Ringden O, Sundberg B, Le Blanc K . Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76: 1208–1213.

    Article  Google Scholar 

  18. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–48.

    Article  Google Scholar 

  19. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O . Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57: 11–20.

    Article  CAS  Google Scholar 

  20. Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.

    Article  CAS  Google Scholar 

  21. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al. Human mesenchymal stem cells modulate B-cell functions. Blood 2006; 107: 367–372.

    Article  CAS  Google Scholar 

  22. Kim N, Im KI, Lim JY, Jeon EJ, Nam YS, Kim EJ et al. Mesenchymal stem cells for the treatment and prevention of graft-versus-host disease: experiments and practice. Ann Hematol 2013; 92: 1295–1308.

    Article  CAS  Google Scholar 

  23. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105: 4120–4126.

    Article  CAS  Google Scholar 

  24. Copland IB, Galipeau J . Death and inflammation following somatic cell transplantation. Semin Immunopathol 2011; 33: 535–550.

    Article  Google Scholar 

  25. Chinnadurai R, Copland IB, Patel SR, Galipeau J . IDO-independent suppression of T cell effector function by IFN-gamma-licensed human mesenchymal stromal cells. J Immunol 2014; 192: 1491–1501.

    Article  CAS  Google Scholar 

  26. Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X et al. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat Med 2011; 17: 1594–1601.

    Article  CAS  Google Scholar 

  27. Krampera M . Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia 2011; 25: 1408–1414.

    Article  CAS  Google Scholar 

  28. Hagmann S, Moradi B, Frank S, Dreher T, Kammerer PW, Richter W et al. Different culture media affect growth characteristics, surface marker distribution and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells. BMC Musculoskelet Disord 2013; 14: 223.

    Article  CAS  Google Scholar 

  29. Introna M, Lucchini G, Dander E, Galimberti S, Rovelli A, Balduzzi A et al. Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients. Biol Blood Marrow Transplant 2014; 20: 375–381.

    Article  Google Scholar 

  30. von Bahr L, Sundberg B, Lonnies L, Sander B, Karbach H, Hagglund H et al. Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant 2012; 18: 557–564.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C), for provision of HLA-A*0201/pp65 (495–503)-tetramer and TC Metrix for HLA-A*0201/IMP (58–66)- and HLA-B*0702 tetramers. This work was supported by the German Ministry of Education and Research (BMBF) as part of the supporting program ‘Cell-Based Regenerative Medicine’ (START-MSC2; funding code 01GN0940 to PW and ADH) and as part of the collaborative research project ‘Systems Biology of Erythropoietin’ (SBEpo; funding code 0316182D to PW and ADH). This work was also supported by the Thiele-Stiftung (funding to ADH) and the German Research Foundation (SFB 873; SP B7 to ADH).

Author Contributions

GM designed and supervised the original research and wrote the original manuscript; NJ performed most of the research and analyzed the data; AH designed new experiments, analyzed data and wrote parts of the resubmitted manuscript; JM, LW and UG performed some research; AS discussed and analyzed flow cytometry data; PW established MSC culture protocols and discussed the manuscript, AD supplied MSC cultures; ADH and BC discussed the manuscript; MS initiated the study, discussed the research and wrote parts of the manuscript.

Author information

Author notes

  1. G Malcherek and N Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany

    G Malcherek, N Jin, A G Hückelhoven, J Mani, L Wang, U Gern, A Diehlmann, P Wuchter, A Schmitt, A D Ho & M Schmitt

  2. Department of Hematology, ZhongDa Hospital, Southeast University, Nanjing, PR China

    N Jin & B Chen

Authors
  1. G Malcherek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A G Hückelhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U Gern
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Diehlmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Wuchter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A D Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Schmitt.

Ethics declarations

Competing interests

PW received honorarium for lectures from Sanofi and consulting fee or honorarium from ETICHO. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malcherek, G., Jin, N., Hückelhoven, A. et al. Mesenchymal stromal cells inhibit proliferation of virus-specific CD8+ T cells. Leukemia 28, 2388–2394 (2014). https://doi.org/10.1038/leu.2014.273

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.273

This article is cited by

Search

Advanced search

Quick links