title: Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA.
abstract: Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft-versus-host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC-induced CD4(+) CD25(+) CD127(-) forkhead box P3 (FoxP3)(+) T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nT(reg)). Perirenal adipose-tissue derived MSC (ASC) obtained from kidney donors induced a 2·1-fold increase in the percentage of CD25(+) CD127(-) FoxP3(+) cells within the CD4(+) T cell population from allostimulated CD25(-/dim) cells. Interleukin (IL)-2 receptor blocking prevented this induction. The ASC-induced T cells (iT(reg)) inhibited effector cell proliferation as effectively as nT(reg). The vast majority of cells within the iT(reg) fraction had a methylated FOXP3 gene T(reg)-specific demethylated region (TSDR) indicating that they were not of nT(reg) origin. In conclusion, ASC induce T(reg) from effector T cells. These iT(reg) have immunosuppressive capacities comparable to those of nT(reg). Their induction is IL-2 pathway-dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de-novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent.
authors.affiliation: Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. a.grohnert@erasmusmc.nl
authors.forename: A U
authors.initials: AU
authors.lastname: Engela
authors.forename: M J
authors.initials: MJ
authors.lastname: Hoogduijn
authors.forename: K
authors.initials: K
authors.lastname: Boer
authors.forename: N H R
authors.initials: NH
authors.lastname: Litjens
authors.forename: M G H
authors.initials: MG
authors.lastname: Betjes
authors.forename: W
authors.initials: W
authors.lastname: Weimar
authors.forename: C C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000077552:Basiliximab; D015704:CD4 Antigens / Q000378:metabolism; D002469:Cell Separation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D019175:DNA Methylation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab
keywords: immunosuppression; induction; interleukin-2 receptor signalling; mesenchymal stem cells; regulatory T cells