Prostaglandin E2 Potentiates Mesenchymal Stem Cell–Induced IL-10+IFN-γ+CD4+ Regulatory T Cells To Control Transplant Arteriosclerosis

Abstract

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 (TR1)–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 TR1-like cells. Both cyclooxygenase-derived PGE2 and IDO help to induce TR1-like cells by MSCs. MSCs constitutively secrete PGE2, which is augmented in allogeneic reactions. However, TR1-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 TR1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced TR1-like cells combined with PGE2, but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: TR1-like cells + PGE2: 11 ± 10%; PGE2 alone: 93 ± 8.7%; TR1-like cells alone: 88 ± 2.4% versus untreated 94 ± 0.9%, p < 0.001). These findings indicate that PGE2 helps MSC-induced IL-10+IFN-γ+CD4+ TR1-like cells inhibit TA. PGE2 combined with MSC-induced TR1-like cells represents a new approach for achieving immune tolerance.

Secretion of immunoregulatory cytokines by mesenchymal stem cells

“…Induction of regulatory T cells is another indirect mechanism for immunoregulation explored by MSCs. IDO expression is responsible for induction of IL-10+IFNγ+CD4+ regulatory T type 1 [T(R)1]-like cells by MSCs [183] . Neutralization of IDO is also a reason for Treg reduction [184] .…”

“…Together with IDO, PGE2 is another major effector molecule responsible for immunoregulatory competence of MSCs [183] . MSCs constitutively produce detectable levels of PGE2 [44,227,228] .…”

“…PGE2 indirectly affects polyclonally or allogenically activated PBMCs by substantial suppression of proliferation and IFNγ secretion [227,229,231] . Simultaneously, the effect on T cells is accompanied by a prevailing bias towards IL-4 production [227] and induction of regulatory IL-10 secreting T cells [183,233] . The influence of MSCs on T cells that represent the effector arm of adaptive immunity is shown to be mediated via the antigen presenting cells (APCs).…”

“…Extremely sensitive to activation signals from the environment, MSCs seem to link the crossroads between innate and adaptive immunity. By suppressing inflammatory mediators, they participate in the activation of feed-back processes, counteracting non-self [55,183] and autoimmune reactivity [233,235,236] , leading the immune system to a steady homeostatic state.…”

Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

“…However, there are also conflicting reports on this subject. Some authors have suggested that MSCs promote the generation of CD4 + CD25 + forkhead box P3 (Foxp3) or CD4 + CD25 high Foxp3 + T-cell populations [7,8,[25][26][27], while others indicate that BMMSCs-induced Tregs populations are not Foxp3 + [4,28]. Apparently, these contradictory findings might be due to the T-cell populations used and the absence or presence of cell contact with BM-MSCs [9].…”