Abstract
BackgroundIn addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs have the ability to modulate the immune response and change the progression of different inflammatory and autoimmune disorders. However, there are still many challenges to overcome before their widespread clinical administration including the mechanisms behind their immunoregulatory function. MSCs inhibit effector T cells and other immune cells, while inducing regulatory T cells (T regs), thus, reducing directly and indirectly the production of pro-inflammatory cytokines. TNF/TNFR signaling plays a dual role: while the interaction of TNFα with TNFR1 mediates pro-inflammatory effects and cell death, its interaction with TNFR2 mediates anti-inflammatory effects and cell survival. Many immunosuppressive cells like T regs, regulatory B cells (B regs), endothelial progenitor cells (EPCs), and myeloid-derived suppressor cells (MDSCs) express TNFR2, and this is directly related to their immunosuppression efficiency. In this article, we investigated the role of the TNFα/TNFR2 immune checkpoint signaling pathway in the immunomodulatory capacities of MSCs.MethodsCo-cultures of MSCs from wild-type (WT) and TNFR2 knocked-out (TNFR2 KO) mice with T cells (WT and TNFα KO) were performed under various experimental conditions.ResultsWe demonstrate that TNFR2 is a key regulatory molecule which is strongly involved in the immunomodulatory properties of MSCs. This includes their ability to suppress T cell proliferation, activation, and pro-inflammatory cytokine production, in addition to their capacity to induce active T regs.ConclusionsOur results reveal for the first time the importance of the TNFα/TNFR2 axis as an active immune checkpoint regulating MSC immunological functions.
Highlights
In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation
To investigate the involvement of the Tumor necrosis factor alpha (TNFα)/Tumor necrosis factor receptor 2 (TNFR2) signaling pathway in the immunoregulatory effect of MSCs, we considered the following facts: (1) MSCs are among the rare population of TNFR2+ cells, and TNFα is important for their activation and immunomodulatory effect
Our results demonstrate for the first time that the TNFα/TNFR2 signaling pathway plays a critical role in the immunomodulatory effect of MSCs directly through higher suppression of T cells and indirectly via induction of more phenotypically active Foxp3+T regs
Summary
In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs are self-renewable, accessible, spindleshaped cells that are expandable in vitro and show exceptional genomic stability [2, 7] Their “stemness” is exemplified by their ability to differentiate, under certain physiological and experimental conditions [8], into multiple mesoderm cell types, including osteocytes, chondrocytes, adipocytes, and smooth muscle cells [9,10,11]. CD105 and CD90 are strongly expressed on the majority of species including murine MSCs but are low on goat and sheep MSCs [16] They must be able to differentiate in vitro into mesoderm cell types [17]
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