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Effect of priming of multipotent mesenchymal stromal cells with interferon γ on their immunomodulating properties

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Abstract

Multipotent mesenchymal stromal cells (MSCs) are widely used for cell therapy, in particular for prophylaxis and treatment of graft-versus-host disease. Due to their immunomodulatory properties, MSCs affect the composition of lymphocyte subpopulations, which depends on the immunological state of the organism and can change in different diseases and during treatment. Administration of MSCs is not always effective. Treatment of MSCs with different cytokines (in particular IFN-γ) leads to enhancement of their immunomodulatory properties. The aim of this study was to investigate sub-populational alterations and activation markers in lymphocytes (activated and non-activated) after interaction with MSCs and MSCs pretreated with IFN-γ (γMSCs) in vitro. Lymphocytes were co-cultured with MSCs or γMSCs for 4 days. The proportion of CD4+ and CD8+ expressing CD25, CD38, CD69, HLA-DR, and PD-1 and distribution of memory and effector subsets were measured by flow cytometry after co-cultivation of lymphocytes with MSCs or γMSCs. The distribution of lymphocyte subpopulations changes during culturing. In non-activated lymphocytes cultured without MSCs, decrease in the proportion of naïve cells and increase in the number of effector cells was observed. That could be explained as activation of lymphocytes in the presence of serum in culturing medium. Co-culturing of lymphocytes with MSCs and γMSCs leads to retention of their non-activated state. Activation of lymphocytes with phytohemagglutinin increases the number of central memory cells and activates marker expression. Interaction with MSCs and γMSCs prevents activation of lymphocytes and keeps their naïve state. Priming with IFN-γ did not induce MSCs inhibitory effect on activation of lymphocytes.

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Abbreviations

APC:

antigen presenting cells

CM:

central memory cells

EM:

effector memory cells

IDO-1:

indoleamine 2,3-dioxygenase

IFN-γ:

interferon gamma

MHC-I(II):

major histocompatibility complex I(II)

MSCs:

multipotent mesenchymal stromal cells

γMSCs:

MSCs pre-treated with IFN-γ

NV:

naïve cells

PBMCs:

peripheral blood mononuclear cells

PHA:

phytohemagglutinin

SCM:

stem central memory cells

TE:

terminal effector cells

TM:

transitional memory cells

Treg :

regulatory T cells

References

  1. Jones, E., and McGonagle, D. (2007) Human bone marrow mesenchymal stem cells in vivo, Rheumatology, 47, 126–131.

    Article  PubMed  Google Scholar 

  2. Le Blanc, K., Rasmusson, I., Gotherstrom, C., Seidel, C., Sundberg, B., Sundin, M., Rosendahl, K., Tammik, C., and Ringden, O. (2004) Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes, Scand. J. Immun., 60, 307–315.

    Article  Google Scholar 

  3. Di Nicola, M., Carlo-Stella, C., Magni, M., Milanesi, M., Longoni, P. D., Matteucci, P., Grisanti, S., and Gianni, A. M. (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli, Blood, 99, 3838–3843.

    Article  PubMed  Google Scholar 

  4. Aggarwal, S., and Pittenger, M. (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses, Blood, 105, 1815–1822.

    Article  CAS  PubMed  Google Scholar 

  5. Wada, N., Bartold, P. M., and Gronthos, S. (2011) Human foreskin fibroblasts exert immunomodulatory properties by a different mechanism to bone marrow stromal/stem cells, Stem Cells Dev., 20, 647–659.

    Article  CAS  PubMed  Google Scholar 

  6. Najar, M., Raicevic, G., Jebbawi, F., De Bruyn, C., Meuleman, N., Bron, D., Toungouz, M., and Lagneaux, L. (2012) Characterization and functionality of the CD200-CD200R system during mesenchymal stromal cell interactions with T-lymphocytes, Immunol. Lett., 146, 50–56.

    Article  CAS  PubMed  Google Scholar 

  7. Akiyama, K., Chen, C., Wang, D., Xu, X., Qu, C., Yamaza, T., Cai, T., Chen, W., Sun, L., and Shi, S. (2012) Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis, Cell Stem Cell, 10, 544–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Augello, A., Tasso, R., Negrini, S., Amateis, A., Indiveri, F., Cancedda, R., and Pennesi, G. (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway, Eur. J. Immunol., 35, 1482–1490.

    Article  CAS  PubMed  Google Scholar 

  9. Polchert, D., Sobinsky, J., Douglas, G., Kidd, M., Moadsiri, A., Reina, E., Genrich, K., Mehrotra, S., Setty, S., Smith, B., and Bartholomew, A. (2008) IFN-γ activa-tion of mesenchymal stem cells for treatment and prevention of graft versus host disease, Eur. J. Immun., 38, 1745–1755.

    Article  CAS  Google Scholar 

  10. Chan, W., Lau, A., Li, J., Law, H., Lau, Y., and Chan, G. (2008) MHC expression kinetics and immunogenicity of mesenchymal stromal cells after short-term IFN-γ challenge, Exp. Hemat., 36, 1545–1555.

    Article  CAS  PubMed  Google Scholar 

  11. Freeman, G., Long, A., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L., Malenkovich, N., Okazaki, T., Byrne, M., Horton, H., Fouser, L., Carter, L., Ling, V., Bowman, M., Carreno, B., Collins, M., Wood, C., and Honjo, T. (2000) Engagement of the Pd-1 immunoin-hibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation, J. Exp. Med., 192, 1027–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Krampera, M., Cosmi, L., Angeli, R., Pasini, A., Liotta, F., Andreini, A., Santarlasci, V., Mazzinghi, B., Pizzolo, G., Vinante, F., Romagnani, P., Maggi, E., Romagnani, S., and Annunziato, F. (2006) Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells, Stem Cells, 24, 386–398.

    Article  CAS  PubMed  Google Scholar 

  13. Sivanathan, K., Gronthos, S., Rojas-Canales, D., Thierry, B., and Coates, P. (2014) Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation, Stem Cell Rev. Rep., 10, 351–375.

    Article  CAS  Google Scholar 

  14. Reddy, M., Eirikis, E., Davis, C., Davis, H. M., and Prabhakar, U. (2004) Comparative analysis of lymphocyte activation marker expression and cytokine secretion profile in stimulated human peripheral blood mononuclear cell cultures: an in vitro model to monitor cellular immune function, J. Immun. Methods, 293, 127–142.

    Article  CAS  Google Scholar 

  15. Mahnke, Y., Brodie, T., Sallusto, F., Roederer, M., and Lugli, E. (2013) The who’s who of T-cell differentiation: human memory T-cell subsets, Eur. J. Immun., 43, 2797–2809.

    Article  CAS  Google Scholar 

  16. Licastro, F., Davis, L., and Morini, M. (1993) Lectins and superantigens: membrane interactions of these compounds with T lymphocytes affect immune responses, Int. J. Biochem., 25, 845–852.

    Article  CAS  PubMed  Google Scholar 

  17. Caruso, A., Licenziati, S., Corulli, M., Canaris, A., De Francesco, M., Fiorentini, S., Peroni, L., Fallacara, F., Dima, F., Balsari, A., and Turano, A. (1997) Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation, Cytometry, 27, 71–76.

    Article  CAS  PubMed  Google Scholar 

  18. Rothstein, D., and Sayegh, M. (2003) T-cell costimulatory pathways in allograft rejection and tolerance, Immun. Rev., 196, 85–108.

    Article  CAS  PubMed  Google Scholar 

  19. Janeway, C., Travers, P., Walport, M., and Shlomchik, M. (2017) Immunobiology: The Immune System in Health and Disease, 6th Edn., Garland Science, NY.

    Google Scholar 

  20. Greaves, M., Janossy, G., and Doenhoff, M. (1974) Selective triggering of human T and B lymphocytes in vitro by polyclonal mitogens, J. Exp. Med., 140, 1–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu, W., Putnam, A., Xu-yu, Z., Szot, G., Lee, M., Zhu, S., Gottlieb, P., Kapranov, P., Gingeras, T., De St. Groth, B., Clayberger, C., Soper, D., Ziegler, S., and Bluestone, J. (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells, J. Exp. Med., 203, 1701–1711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Petinati, N. A., Kapranov, N. M., Bigil’deev, A. E., Popova, M. D., Davydova, Y. O., Gal’tseva, I. V., Drize, N. I., Kuzmina, L. A., Parovichnikova, E. N., and Savchenko, V. G. (2017) Changing the properties of multipotent mesenchymal stromal cells by IFNγ administration, Bull. Exp. Mol. Biol. Med., 163, 230–234.

    Article  CAS  Google Scholar 

  23. Kapranov, N., Davydova, Y., Galtseva, I., Bakshinskayte, M., Petinati, N., Drize, N., Kuzmina, L., Parovichnikova, E., and Savchenko, V. (2017) Alterations of multipotent mesenchymal stromal cells induced by interaction with allogeneic lymphocytes in vitro, Int. J. Stem Cell Res. Transplant., 5, 277–286.

    Google Scholar 

  24. Najar, M., Raicevic, G., Fayyad-Kazan, H., Bron, D., Toungouz, M., and Lagneaux, L. (2016) Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells, Cytotherapy, 18, 160–171.

    Article  CAS  PubMed  Google Scholar 

  25. Wang, Y., Chen, X., Cao, W., and Shi, Y. (2014) Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications, Nat. Immun., 15, 1009–1016.

    Article  CAS  Google Scholar 

  26. Klinker, M., Marklein, R., Lo Surdo, J., Wei, C., and Bauer, S. (2017) Morphological features of IFN-γ-stimu-lated mesenchymal stromal cells predict overall immuno-suppressive capacity, Proc. Natl. Acad. Sci. USA, 114, 2598–2607.

    Article  Google Scholar 

  27. Giuliani, M., Poggi, A., and Bennaceur Griscelli, A. (2014) IFN-gamma priming protects fetal and embryonic MSC from NK cell-mediated killing and improves their immunosuppressive properties: role of activating and inhibitory receptors, J. Cell Sci. Ther., 5, 164.

    Google Scholar 

  28. Noone, C., Kihm, A., English, K., O’Dea, S., and Mahon, B. (2013) IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro, Stem Cells Dev., 22, 3003–3014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Waterman, R., Tomchuck, S., Henkle, S., and Betancourt, A. (2010) A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype, PLoS One, 5, e10088.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mareschi, K., Castiglia, S., Sanavio, F., Rustichelli, D., Muraro, M., Defedele, D., Bergallo, M., and Fagioli, F. (2016) Immunoregulatory effects on T lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta, Exp. Hematol., 44, 138–150.

    Article  CAS  PubMed  Google Scholar 

  31. Yan, Z., Zhuansun, Y., Liu, G., Chen, R., Li, J., and Ran, P. (2014) Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions, Immunol. Lett., 162, 248–255.

    Article  CAS  PubMed  Google Scholar 

  32. Cao, W., Cao, K., Cao, J., Wang, Y., and Shi, Y. (2015) Mesenchymal stem cells and adaptive immune responses, Immunol. Lett., 168, 147–153.

    Article  CAS  PubMed  Google Scholar 

  33. Lysak, D., Koutova, L., Holubova, M., Vlas, T., Miklikova, M., and Jindra, P. (2016) The quality control of mesenchymal stromal cells by in vitro testing of their immunomodulatory effect on allogeneic lymphocytes, Folia Biol. (Praha), 62, 120–130.

    CAS  Google Scholar 

  34. Chinnadurai, R., Copland, I., Garcia, M., Petersen, C., Lewis, C., Waller, E., Kirk, A., and Galipeau, J. (2016) Cryopreserved mesenchymal stromal cells are susceptible to T-cell mediated apoptosis which is partly rescued by IFNγ licensing, Stem Cells, 34, 2429–2442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Duijvestein, M., Wildenberg, M., Welling, M., Hennink, S., Molendijk, I., Van Zuylen, V., Bosse, T., Vos, A., De Jonge-Muller, E., Roelofs, H., Van der Weerd, L., Verspaget, H., Fibbe, W., te Velde, A., Van den Brink, G., and Hommes, D. (2011) Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis, Stem Cells, 29, 1549–1558.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. National Research Center for Hematology, Ministry of Healthcare of the Russian Federation, 125167, Moscow, Russia

    N. M. Kapranov, Y. O. Davydova, I. V. Galtseva, N. A. Petinati, N. I. Drize, L. A. Kuzmina, E. N. Parovichnikova & V. G. Savchenko

Authors
  1. N. M. Kapranov
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  2. Y. O. Davydova
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  3. I. V. Galtseva
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  4. N. A. Petinati
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  5. N. I. Drize
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  6. L. A. Kuzmina
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  7. E. N. Parovichnikova
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  8. V. G. Savchenko
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Correspondence to N. M. Kapranov.

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Published in Russian in Biokhimiya, 2017, Vol. 82, No. 10, pp. 1510-1521.

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Kapranov, N.M., Davydova, Y.O., Galtseva, I.V. et al. Effect of priming of multipotent mesenchymal stromal cells with interferon γ on their immunomodulating properties. Biochemistry Moscow 82, 1158–1168 (2017). https://doi.org/10.1134/S000629791710008X

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  • DOI: https://doi.org/10.1134/S000629791710008X

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