IDO Expression In Human Mesenchymal Stromal Cells Mediates T Cell Suppression and Leads to Monocyte Differentiation Into IL-10 Secreting Immunosuppressive CD206⁺ M2 Macrophages

Abstract 2784

Clinical trials testing the use of either autologous or allogeneic human bone marrow-derived mesenchymal stromal cells (MSC) as a cell-based pharmaceutical for suppression of autoimmune and alloimmune ailments are underway. Reported results from completed trials vary in effectiveness within and between studies without any clear mechanistic explanation. We propose that these discrepancies may arise from intrinsic variability in the immunosuppressive potential of each MSC donor source. Here, we demonstrate that TNF-a and IFN-g-activated MSC derived from normal adult volunteers suppress T cell proliferation in vitro in a variegated manner, where high IDO producers were more efficient inhibitor of T cell proliferation. We also demonstrate that MSC IDO activity induce the differentiation of monocytes into IL-10 secreting M2 immunosuppressive macrophages (CD14⁺/CD206⁺). More precisely, tryptophan metabolite kynurenine, derived from the enzymatic activity of IDO induces the conversion of monocytes into M2 macrophages. Those monocyte-derived M2 in turn suppressed T cell proliferation in an IL-10 dependent and independent manner, thus amplifying the immunosuppressive effect generated by MSC. In summary, the immune plasticity of IFN-g and TNF-α licensed veto MSCs varies amongst donors and defines a central role to inducible IDO activity and its bystander effects on lymphomyeloid immune effectors.