Prostaglandin E₂ potentiates mesenchymal stem cell-induced IL-10⁺IFN-γ⁺CD4⁺ regulatory T cells to control transplant arteriosclerosis

Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow- derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10⁺ and IFN-γ⁺ cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL-10⁺IFN-γ⁺CD4 ⁺ regulatory T type 1 (T_R1)-like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10⁺IFN- γ⁺CD4⁺ cells, which confer resistance to allogeneic proliferation in an IL-10-dependent manner, resemble T_R1-like cells. Both cyclooxygenase-derived PGE₂ and IDO help to induce T _R1-like cells by MSCs. MSCs constitutively secrete PGE₂, which is augmented in allogeneic reactions. However, T_R1-like cells were deficient in PGE₂ and 4-fold less potent than were MSCs in suppressing MLR. PGE₂ mimetic supplements can enhance the immunosuppressive potency of T_R1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced T_R1-like cells combined with PGE₂, but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: T_R1-like cells + PGE₂: 11 6 10%; PGE₂ alone: 93 6 8.7%; T _R1-like cells alone: 88 6 2.4% versus untreated 94 6 0.9%, p < 0.001). These findings indicate that PGE₂ helps MSC-induced IL-10⁺IFN-γ⁺CD4⁺ T_R1-like cells inhibit TA. PGE₂ combined with MSC-induced T_R1-like cells represents a new approach for achieving immune tolerance.