Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.
Infusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)-10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell-suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.
Beyth
Shaul
S
Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel.
Borovsky
Zipora
Z
Mevorach
Dror
D
Liebergall
Meir
M
Gazit
Zulma
Z
Aslan
Hadi
H
Galun
Eithan
E
Rachmilewitz
Jacob
J
D000938:Antigen-Presenting Cells / Q000166:cytology*; D001773:Blood Cells; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology