Immunogenicity of human mesenchymal stem cells in HLA-class I-restricted T-cell responses against viral or tumor-associated antigens.
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)-gamma 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-gamma. 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-gamma. 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.
Morandi
Fabio
F
Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy. fabiomorandi@ospedale-gaslini.ge.it
Raffaghello
Lizzia
L
Bianchi
Giovanna
G
Meloni
Francesca
F
Salis
Annalisa
A
Millo
Enrico
E
Ferrone
Soldano
S
Barnaba
Vincenzo
V
Pistoia
Vito
V
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053804:Granzymes / Q000037:antagonists & inhibitors; D006680:HLA Antigens / Q000276:immunology; D059951:HLA-G Antigens; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D015843:Serpins / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C102316:SERPINB9 protein, human; D015843:Serpins; D007371:Interferon-gamma; D053804:Granzymes