Immunogenicity of Human Mesenchymal Stem Cells in HLA-Class I-Restricted T-Cell Responses Against Viral or Tumor-Associated Antigens

  • Morandi F
  • Raffaghello L
  • Bianchi G
  • et al.
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Abstract

Human mesenchymal stem cells (MSC) are immunosuppressive and poorly immunogenic but may act as antigen-presenting cells (APC) for CD4+ T-cell responses; here we have investigated their ability to serve as APC for in vitro CD8+ T-cell responses. MSC pulsed with peptides from viral antigens evoked interferon (IFN)-γ and Granzyme B secretion in specific cytotoxic T lymphocytes (CTL) and were lysed, although with low efficiency. MSC transfected with tumor mRNA or infected with a viral vector carrying the Hepatitis C virus NS3Ag gene induced cytokine release but were not killed by specific CTL, even following pretreatment with IFN-γ. To investigate the mechanisms involved in MSC resistance to CTL-mediated lysis, we analyzed expression of human leukocyte antigen (HLA) class I-related antigen-processing machinery (APM) components and of immunosuppressive HLA-G molecules in MSC. The LMP7, LMP10, and ERp57 components were not expressed and the MB-1 and zeta molecules were downregulated in MSC either unmanipulated or pretreated with IFN-γ. Surface HLA-G was constitutively expressed on MSC but was not involved in their protection from CTL-mediated lysis. MSC supernatants containing soluble HLA-G (sHLA-G) inhibited CTL-mediated lysis, whereas those lacking sHLA-G did not. The role of sHLA-G in such inhibition was unambiguously demonstrated by partial restoration of lysis following sHLA-G depletion from MSC supernatants. In conclusion, human MSC can process and present HLA class I-restricted viral or tumor antigens to specific CTL with a limited efficiency, likely because of some defects in APM components. However, they are protected from CTL-mediated lysis through a mechanism that is partly sHLA-G-dependent.Disclosure of potential conflicts of interest is found at the end of this article.

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Morandi, F., Raffaghello, L., Bianchi, G., Meloni, F., Salis, A., Millo, E., … Pistoia, V. (2008). Immunogenicity of Human Mesenchymal Stem Cells in HLA-Class I-Restricted T-Cell Responses Against Viral or Tumor-Associated Antigens. Stem Cells, 26(5), 1275–1287. https://doi.org/10.1634/stemcells.2007-0878

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