Soluble mediators from mesenchymal stem cells suppress T cell proliferation by inducing IL-10

Seung-Ha Yang,Chung-Gyu Park,Bongi Kim,Min-Jung Park,Yong-Hee Kim,Jin-Young Shin,So-Hee Hong,Il-Hee Yoon,Hye-Young Nam,Su-Young Kim

doi:10.3858/emm.2009.41.5.035

Seung-Ha Yang, Chung-Gyu Park + Show 8 more

Open Access

https://doi.org/10.3858/emm.2009.41.5.035

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Abstract

Mesenchymal stem cells (MSCs) can inhibit T cell proliferation; however, the underlying mechanisms are not clear. In this study, we investigated the mechanisms of the immunoregulatory activity of MSCs on T cells. Irradiated MSCs co-cultured with either na?ve or pre-activated T cells in a mixed lymphocyte reaction (MLR) significantly suppressed T cell proliferation in a dose-dependent manner, irrespective of allogeneic disparity between responders and MSCs. Transwell assays revealed that the suppressive effect was primarily mediated by soluble factors that induced apoptosis. Splenocytes stimulated with alloantigen in the presence of the MSC culture supernatant (CS) produced a significant amount of IL-10, which was attributed to an increase in the number of IL-10 secreting cells, confirmed by an ELISPOT assay. The blockade of IL-10 and IL-10 receptor interaction by anti-IL-10 or anti-IL-10-receptor antibodies abrogated the suppressive capacity of MSC CS, indicating that IL-10 plays a major role in the suppression of T cell proliferation. The addition of 1-methyl-DL-tryptophan (1-MT), an indoleamine 2,3-dioxygenase (IDO) inhibitor, also restored the proliferative capacity of T cells. In conclusion, we demonstrated that soluble mediators from culture supernatant of MSCs could suppress the proliferation of both naive and pre-activated T cells in which IL-10 and IDO play important roles.

Highlights

To investigate the ability of mesenchymal stem cell (MSC) to suppress T cell proliferation, different doses of MSCs were added to mixed lymphocyte reaction (MLR) with a ratio of splenocyte to MSCs of 2,000:1, 200:1 or 20:1
To determine whether the suppression of T cell proliferation by MSCs or MSC culture supernatant (CS) was due to the induction of cell death or cell cycle arrest, we examined whether MSC CS could delay the cell cycle or trigger apoptosis of splenocytes by estimating values of each cell-cycle phase
Because IL-10 is a well known inhibitor of T cell proliferation and activation, we investigated whether T cell proliferation recovered when MSC CS was used in MLR with blocking antibodies for either IL-10 or IL-10 receptor

Summary

Introduction

Mesenchymal stem cells (MSCs) are multipotential non-hematopoietic cells (Wakitani et al, 1995; Pittenger et al, 1999) that can expand ex vivo without any particular changes in phenotype and function (Reyes et al, 2001) and differentiate in vitro into several mesenchymal cell lineages such as adipocytes, chondrocytes, osteocytes, myocytes, astrocytes and neurons (Krampera et al, 2003; Kato et al, 2004; Glennie et al, 2005; Zappia et al, 2005; Nauta et al, 2006; Stagg et al, 2006). Aggarwal and Pittenger (2005) showed that MSCs altered the phenotype of specific immune cells, providing evidence that transplantation of allogeneic MSCs could be clinically applicable Despite all of this evidence for the therapeutic potential of MSCs, in order for MSCs to be accepted broadly as a therapeutic modality, the exact molecular mechanisms underlying their suppressive ability should be more fully understood. Evidence from in vitro stimulation tests has demonstrated that both cell-cell contact and

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