Requirement of IFN-γ–Mediated Indoleamine 2,3-Dioxygenase Expression in the Modulation of Lymphocyte Proliferation by Human Adipose–Derived Stem Cells

Abstract

Human adipose-derived mesenchymal stem cells (hASCs) are mesenchymal stem cells (MSCs) with reduced immunogenicity and capability to modulate immune responses. Whereas the immunosuppressive activity of bone marrow-MSCs has received considerable attention during the last few years, the specific mechanisms underlying hASC-mediated immunosuppression have been poorly studied. Recent studies comparing both cell types have reported differences at transcriptional and proteomic levels, suggesting that hASCs and bone marrow-MSCs, while having similarities, are quite different. This suggests that different mechanisms of immunosuppression may apply. Here, we report that hASCs inhibit peripheral blood mononuclear cells (PBMCs), and CD4(+) and CD8(+) T cell proliferation in both cell-cell contact and transwell conditions, which is accompanied by a reduction of proinflammatory cytokines. We demonstrate that hASCs do not constitutively express immunomodulatory factors. Conditioned supernatants from hASCs stimulated by IFN-gamma, PBMCs, or activated PBMCs highly inhibited PBMC proliferation, indicating that inhibitory factors are released upon hASC activation. Many factors have been involved in MSC-mediated immunosuppression, including IFN-gamma, IL-10, hepatocyte growth factor, prostaglandin E2, transforming growth factor-beta1, indoleamine 2,3-dioxygenase (IDO), nitric oxide, and IL-10. Using pharmacological inhibitors, neutralizing antibodies, and genetically modified hASCs that constitutively express or silence IDO enzyme, we demonstrate that, in the case of hASCs, the IFN-gamma/IDO axis is essential. Taken together, our data support the key role of IDO in the therapeutic use of hASC on immunomediated diseases.

Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

“…However, in 2 separate studies the cell-cell contact requirement was corroborated [30] and disputed [31], respectively. Regardless of this disagreement, the immunosuppressive effect of ADSC has been consistently observed in all subsequent relevant studies [32][33][34][35][36]. Further, in a comparative study, ADSC and BMSC were found to exhibit the same pattern of immunologically relevant surface markers (MHC-I, MHC-II, CD40, and CD40L) [37].…”

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…MSCs do not secrete immunomodulatory proteins in the absence of activation [4,5]. In vitro, activated T cells, individual or combinations of cytokines such as interferon-γ (IFNγ) or TNFα are used to activate MSCs [5].…”

“…MSCs act as pleiotropic immune regulators to suppress immune responses through the production of multiple soluble factors and/or direct cell-cell contact in order to affect all the actors of immune responses: T cells, NK cells, B cells and DCs [4,28]. MSCs may act locally, however they may also accumulate in secondary lymphoid organs and attenuate delayed-type hypersensitivity response by inducing apoptotic cell death of surrounding immune cells in the draining lymph node.…”

“…Human MSCs express the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), known to suppress T-cell responses [4,5,26]. IDO has been implicated in the induction of tolerogenic DCs, the switch to a Th2-dominant cytokine inflammatory response and the induction of Tregs.…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…MSCs employ these immunosuppressive effects via different soluble molecules including TGF-b, indoleamine 2,3-dioxygenase (IDO), inducible Nitric oxide synthases (iNOS), PGE2, IL-1 receptor antagonist and Tumour necrosis factor-inducible gene 6 (TSG6) [65][66][67][68]. Recently, other mechanisms of MSC-dependent immunomodulation have been described.…”