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

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 CD 4 + CD 25 + CD 127 – forkhead box P3 ( FoxP 3) + T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (n T reg ). Perirenal adipose‐tissue derived MSC ( ASC ) obtained from kidney donors induced a 2·1‐fold increase in the percentage of CD 25 + CD 127 – FoxP 3 + cells within the CD 4 + T cell population from allostimulated CD 25 –/dim cells. Interleukin ( IL) ‐2 receptor blocking prevented this induction. The ASC ‐induced T cells (i T reg ) inhibited effector cell proliferation as effectively as n T reg . The vast majority of cells within the i T reg fraction had a methylated FOXP3 gene T reg‐specific demethylated region ( TSDR ) indicating that they were not of n T reg origin. In conclusion, ASC induce T reg from effector T cells. These i T reg have immunosuppressive capacities comparable to those of n T 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.