Abstract
Cell-cell adhesion mediated by ICAM-1 and VCAM-1 is critical for T cell activation and leukocyte recruitment to the inflammation site and, therefore, plays an important role in evoking effective immune responses. However, we found that ICAM-1 and VCAM-1 were critical for mesenchymal stem cell (MSC)-mediated immunosuppression. When MSCs were cocultured with T cells in the presence of T cell Ag receptor activation, they significantly upregulated the adhesive capability of T cells due to the increased expression of ICAM-1 and VCAM-1. By comparing the immunosuppressive effect of MSCs toward various subtypes of T cells and the expression of these adhesion molecules, we found that the greater expression of ICAM-1 and VCAM-1 by MSCs, the greater the immunosuppressive capacity that they exhibited. Furthermore, ICAM-1 and VCAM-1 were found to be inducible by the concomitant presence of IFN-gamma and inflammatory cytokines (TNF-alpha or IL-1). Finally, MSC-mediated immunosuppression was significantly reversed in vitro and in vivo when the adhesion molecules were genetically deleted or functionally blocked, which corroborated the importance of cell-cell contact in immunosuppression by MSCs. Taken together, these findings reveal a novel function of adhesion molecules in immunoregulation by MSCs and provide new insights for the clinical studies of antiadhesion therapies in various immune disorders.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Neutralizing / immunology
-
Antibodies, Neutralizing / pharmacology
-
Cells, Cultured
-
Coculture Techniques
-
Culture Media, Conditioned / pharmacology
-
Female
-
Flow Cytometry
-
Immunosuppression Therapy
-
Inflammation Mediators / immunology
-
Inflammation Mediators / metabolism*
-
Intercellular Adhesion Molecule-1 / genetics
-
Intercellular Adhesion Molecule-1 / metabolism*
-
Interferon gamma Receptor
-
Interferon-gamma / immunology
-
Interferon-gamma / metabolism
-
Interleukin-1 / immunology
-
Interleukin-1 / metabolism
-
Male
-
Mesenchymal Stem Cells / drug effects
-
Mesenchymal Stem Cells / immunology
-
Mesenchymal Stem Cells / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Receptors, Interferon / genetics
-
Receptors, Interferon / metabolism
-
Receptors, Tumor Necrosis Factor, Type I / genetics
-
Receptors, Tumor Necrosis Factor, Type I / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Spleen / cytology
-
Spleen / immunology
-
Spleen / metabolism
-
T-Lymphocytes / immunology
-
T-Lymphocytes / metabolism
-
Tumor Necrosis Factor-alpha / immunology
-
Tumor Necrosis Factor-alpha / metabolism
-
Vascular Cell Adhesion Molecule-1 / genetics
-
Vascular Cell Adhesion Molecule-1 / metabolism*
Substances
-
Antibodies, Neutralizing
-
Culture Media, Conditioned
-
Inflammation Mediators
-
Interleukin-1
-
Receptors, Interferon
-
Receptors, Tumor Necrosis Factor, Type I
-
Tumor Necrosis Factor-alpha
-
Vascular Cell Adhesion Molecule-1
-
Intercellular Adhesion Molecule-1
-
Interferon-gamma