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First published online February 21, 2008
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Submitted on October 18, 2007
Accepted on February 13, 2008

TISSUE-SPECIFIC STEM CELLS

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

Fabio Morandi 1*, Lizzia Raffaghello 1, Giovanna Bianchi 1, Francesca Meloni 2, Annalisa Salis 3, Enrico Millo 3, Soldano Ferrone 4, Vincenzo Barnaba 2, Vito Pistoia 1

1 Laboratory of Oncology, G.Gaslini Children's Hospital, Genoa, Italy
2 Dipartimento di Medicina Interna, Università degli Studi di Roma La Sapienza, Rome, Italy
3 Centro di Eccellenza per Ricerche Biomediche, University of Genoa, Genoa, Italy
4 Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213

* To whom correspondence should be addressed. E-mail: fabiomorandi{at}ospedale-gaslini.ge.it.


  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 IFN-{gamma} and Granzyme B secretion in specific 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 pre-treatment with IFN-{gamma}.

To investigate the mechanisms involved in MSC resistance to CTL mediated lysis, we analysed expression of HLA class I related antigen-processing machinery (APM) components and of immunosuppressive HLA-G molecules in MSC. The LMP7, LMP10 and ERP-57 components were not expressed and the MB-1 and zeta molecules were downregulated in MSC either unmanipulated or pre-treated with IFN-{gamma}.

Surface HLA-G was constitutively expressed on MSC, but not involved in their protection from CTL-mediated lysis. MSC supernatants containing soluble (s)HLA-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 due to some defects in APM components. However, they are protected from CTL-mediated lysis through a mechanism that is partly sHLA-G dependent.

 Key Words. antigen presenting cells, antigen processing machinery, CTL, immunogenicity, MSC






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