Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 42; pp. 17384 - 17389
• Main Authors: Chiesa, Sabrina, Morbelli, Silvia, Morando, Sara, Massollo, Michela, Marini, Cecilia, Bertoni, Arinna, Frassoni, Francesco, Bartolomé, Soraya Tabera, Sambuceti, Gianmario, Traggiai, Elisabetta, Uccelli, Antonio
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.10.2011; National Acad Sciences
• Subjects: Animal migration behavior; Animals; Antigen Presentation; Antigens; Biological Sciences; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - immunology; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cell Movement - immunology; Coculture Techniques; Cytokines; Cytokines - genetics; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - physiology; Dendritic Cells - transplantation; Gene Expression; immunomodulation; intravenous injection; Intravenous injections; Lymph nodes; Lymph Nodes - cytology; Lymph Nodes - immunology; Mesenchymal stem cells; Mesenchymal Stromal Cells - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; mitogen-activated protein kinase; Molecules; Phosphorylation; Rodents; secretion; Signal Transduction - immunology; Stem cells; T cell receptors; T lymphocytes; T-Lymphocytes - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1103650108

Dendritic cells (DC) are highly specialized antigen-presenting cells characterized by the ability to prime T-cell responses. Mesenchymal stem cells (MSC) are adult stromal progenitor cells displaying immunomodulatory activities including inhibition of DC maturation in vitro. However, the specific impact of MSC on DC functions, upon in vivo administration, has never been elucidated. Here we show that murine MSC impair Toll-like receptor-4 induced activation of DC resulting in the inhibition of cytokines secretion, down-regulation of molecules involved in the migration to the lymph nodes, antigen presentation to CD4+ T cells, and cross-presentation to CD8+ T cells. These effects are associated with the inhibition of phosphorylation of intracellular mitogen-activated protein kinases. Intravenous administration of MSC decreased the number of CCR7 and CD49dβ1 expressing CFSE-labeled DC in the draining lymph nodes and hindered local antigen priming of DO11.10 ovalbumin-specific CD4+ T cells. Upon labeling of DC with technetium-99m hexamethylpropylene amine oxime to follow their in vivo biodistribution, we demonstrated that intravenous injection of MSC blocks, almost instantaneously, the migration of subcutaneously administered ovalbumin-pulsed DC to the draining lymph nodes. These findings indicate that MSC significantly affect DC ability to prime T cells in vivo because of their inability to home to the draining lymph nodes and further confirm MSC potentiality as therapy for immune-mediated diseases.