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Abstract
The physiological role of mesenchymal stem cells (MSCs) is to provide a source of cells to replace mesenchymal-derivatives in stromal tissues with high cell turnover or following stromal tissue damage to elicit repair. Human MSCs have been shown to suppress in vitro T-cell responses via a number of mechanisms including indoleamine 2,3-dioxygenase (IDO). This immunomodulatory capacity is likely to be related to their in vivo function in tissue repair where local, transient suppression of immune responses would benefit differentiation. Further understanding of the impact of locally modulated immune responses by MSCs is hampered by evidence that IDO is not produced or utilized by mouse MSCs. In this study, we demonstrate that IDO-mediated tryptophan starvation triggered by human MSCs inhibits T-cell activation and proliferation through induction of cellular stress. Significantly, we show that despite utilizing different means, immunomodulation of murine T-cells also involves cellular stress and thus is a common strategy of immunoregulation conserved between mouse and humans.
Highlights
Mesenchymal stem cells (MSCs) is the generic name given to tissue-resident adult stromal stem cells that are capable of differentiating into a number of mesodermal lineages in vitro [1]
In corroboration with published findings we found that the inhibition of proliferation of αCD3/ CD28 activated CD4+ T-cells by both Dental pulp (mesenchymal) stem cells (dpMSCs) and bone marrow mesenchymal stem cells (bmMSCs) could be partially reversed through the addition of the IDO inhibitor L-1MT, but not D-1MT (Fig 1A)
In order to distinguish between these two mechanisms, we were able to utilize the tight regulatory control of IDO expression in mesenchymal stem cells (MSCs) by IFNγ [24] and analyse the ability of T cells to proliferate in supernatants from IFN-γ-activated IDO+ dpMSCs versus non-activated IDO- dpMSC (CM) supernatants (Fig 1B)
Summary
Mesenchymal stem cells (MSCs) is the generic name given to tissue-resident adult stromal stem cells that are capable of differentiating into a number of mesodermal lineages in vitro [1]. In addition to their ‘stem cell properties’, MSCs have been shown to exhibit broad and potent immunomodulatory effects in vitro and in vivo [2,3,4,5,6,7]. The effectiveness of MSC-based immunotherapies has been challenged by recent observations showing that systemically delivered MSCs rapidly undergo apoptosis caused by T cell cytotoxicity and accumulate in the lungs where they undergo apoptosis [12,13].
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