Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells.
Adult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogeneic cell therapy a possibility. The exact mechanisms involved in regulatory T cell induction by allogeneic human MSC was examined, using purified CD4+ populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)+ and CD25+ mRNA and protein expression in CD4+ T cells. This phenomenon required direct contact between MSC and purified T cells, although cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-beta1 were shown to have a non-redundant role in the induction of CD4+CD25+FoxP3+ T cells. Purified CD4+CD25+ T cells induced by MSC co-culture expressed TGF-beta1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T cell induction involving direct MSC contact with CD4+ cells followed by both prostaglandin E(2) and TGF-beta1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving allogeneic MSC.
English
K
K
Institute of Immunology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
Ryan
J M
JM
Tobin
L
L
Murphy
M J
MJ
Barry
F P
FP
Mahon
B P
BP
D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D015232:Dinoprostone