Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA

Abstract

Summary 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 (nTreg). 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 (iTreg) inhibited effector cell proliferation as effectively as nTreg. The vast majority of cells within the iTreg fraction had a methylated FOXP3 gene Treg-specific demethylated region (TSDR) indicating that they were not of nTreg origin. In conclusion, ASC induce Treg from effector T cells. These iTreg have immunosuppressive capacities comparable to those of nTreg. 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.