Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Abstract

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR stimulation of T cells. Inhibition of NF-κB through silencing of IκB kinase β or the TNF-α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC-associated NF-κB activation primarily leads to inhibition of T-cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF-α/NF-κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF-κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic. Keywords:Immunoregulation r MSC r NF-κB r TNF-α See accompanying Commentary by Pistoia and RaffaghelloAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMesenchymal stromal cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into multiple lineages. These cells are found in a variety of tissues during development, of which BM represents the most common source for research purposes. From a clinical perspective, MSCs are considered to Correspondence: Dr. César Trigueros e-mail: ctrigueros@inbiomed.org have a potential use in tissue repair for bone, cartilage and tendon. However, due to their immunomodulatory properties and their inclusion as a stromal component of the marrow microenvironment, MSCs are currently utilised in other therapeutic scenarios, such as those encountered in hematopoietic stem cell transplantation, GVH disease or chronic inflammatory diseases [1,2]. These characteristics, together with their low immunogenicity [1,2], have opened up promising new avenues of research for the use of MSCs not only in autologous but also in allogeneic settings.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 480-488 Immunomodulation 481 The immunomodulatory activity of MSCs, directed against a wide range of effector cells of both the innate and adaptive immune system, has been described. Communication between MSCs and immune cells, through cell-to-cell contact-dependent and/or contact-independent mechanisms, has been shown to lead to increased production of soluble immunomodulatory factors such as indoleamine 2,3-deoxigenase [3,4], prostaglandin E2 [5][6][7], iNOS [8], transforming growth factor β (TGF-β), hepatocyte growth factor [9], human lymphocytes Ag molecule 5 and IL-10 [10]. Thus, the picture is complex, as it is likely that multiple regulatory mechanisms exist without an obvious hierarchy of importance.The inflammatory e...

PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

“…Moreover, we demonstrate that PPARβ/δ −/− MSCs with enhanced immunosuppressive capacities display a significantly higher NF-κB activity both at steady state and upon activation with proinflammatory cytokines. This is consistent with the inhibitory action of PPARs on NF-κB signalling pathways described in immune cells that is associated with their anti-inflammatory properties2 and the TNF-α-mediated NF-κB activation involved in the immunomodulatory activity of MSCs 34. In this latter study, the authors described that the impairment of NF-κB activation antagonises the inhibitory effect of MSCs on T cell proliferation.…”

“…Since PPARβ/δ acts as a negative regulator of NF-κB activity,2 and that immunosuppression is mediated by activation of NF-κB in MSCs,34 we examined the activity of NF-κB in both PPARβ/δ +/+ and PPARβ/δ −/− MSCs. Using the luciferase-based reporter system, we demonstrated that PPARβ/δ −/− MSCs displayed a significantly higher NF-κB activity than PPARβ/δ +/+ MSCs (figure 6A).…”

Mechanisms of T-Cell Immunosuppression by Mesenchymal Stromal Cells: What Do We Know So Far?

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