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TISSUE-SPECIFIC STEM CELLS

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

^aLaboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy;
^bDipartimento di Medicina Interna, Università degli Studi di Roma La Sapienza, Rome, Italy;
^cCentro di Eccellenza per Ricerche Biomediche, University of Genoa, Genoa, Italy;
^dHillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA

Key Words. Antigen-presenting cells • Antigen-processing machinery • CTL • Immunogenicity • Mesenchymal stem cell

Correspondence: Fabio Morandi, Ph.D., Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genova, Italy. Telephone: 39-010-5636342; Fax: 39-010-3779820; e-mail: fabiomorandi{at}ospedale-gaslini.ge.it

Received October 18, 2007; accepted for publication February 13, 2008.
First published online in STEM CELLS EXPRESS   February 21, 2008.



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)- 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-. 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-. 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.