Purinergic Signal. 2014;10(2):357-65. doi: 10.1007/s11302-013-9385-0.

CD39-mediated effect of human bone marrow derived mesenchymal stem cells on the human Th17 cell function

 

Jong Joo Lee M.D 1,2, Hyun Jeong Jeong 2, Mee Kum Kim M.D, Ph.D 1,2, Won Ryang Wee M.D,Ph.D 1,2, Won Woo Lee Ph.D 3, Seung U. Kim Ph.D 4,5, Changmin Sung6, Yung Hun Yang Ph.D7

1Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea

2Laboratory of corneal regenerative medicine and ocular immunology, Seoul Artificial Eye Center, Seoul National University Hospital Clinical Research Institute, Seoul, Korea

3Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea

4Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea

5Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

6Interdisciplinary Program of Bioengineering, Seoul National University, Seoul, Korea

7Department of Microbial Engineering, College of Engineering, Konkuk University, Seoul, Korea

 

Address correspondence to: Mee Kum Kim, M.D., PhD.

Department of Ophthalmology, Seoul National University College of Medicine

103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea

E-mail: kmk9@snu.ac.kr Tel. 82-2-2072-2665 Fax. 82-2-741-3187

 

Abstract

Backgrounds : In human BMSCs, immunosuppression is mediated by direct cell-to-cell contact or by the paracrine pathways. Recent studies provide evidences that CD39 mediated the immune suppression of T cells by MSCs in a cell-to-cell contact manner.

Purpose : To investigate the immune-modulatory effects of human bone marrow derived mesenchymal stem cells (hBMSCs) on human Th17 cells through the CD39 mediated pathway.

Methods : The suppressive effects of hBMSCs were evaluated by assessing their effects on the proliferation of Th17 cells and the secretion of interferon (IFN)-γ and interleukin (IL)-17A by Th17 cells with or without anti-CD39 treatment. The change of CD73 expression on the T cells with or without co-culture of hBMSCs was evaluated by flow cytometry or DNA microarray. The changes of adenosine production with or without anti-CD39 treatment were assessed by mass spectrometry.

Results : hBMSCs effectively suppressed the secretion of both IFN-γ and IL-17A from Th17 cells which was accompanied by increased adenosine production, while anti-CD39 treatment significantly reduced the inhibitory effects of hBMSCs on the proliferation and secretion of the Th17 cells. The hBMSCs induced increased expression of the CD39 and CD73 on T cells correlated with the suppressive function of hBMSCs

Conclusion : Our data suggests that hBMSCs can effectively suppress Th17 cells via the CD39-CD73-mediated adenosine-producing pathway.

Keywords: Bone marrow derived mesenchymal stem cells, Th17 cells, CD39, CD73, Interleukin 17, Interferon g, adenosine

PMID: 24043462

 

Supplementary

The purpose of this study is to investigate whether   immune response of Th17 cells may be inhibited by BMSCs, mediated by CD39 -dependent promotion of adenosine signaling.

Our data showed that (1) CD39 and CD73 expression up-regulation on T cells   during co-culture with hBMSCs, (2) hBMSCs suppressed Th17 cells proliferation via up-regulation of CD39 expression, (3) hBMSCs significantly attenuated IL-17A/ IFNγ secretion in Th 17 cells via up-regulation of CD39 expression, and (4) Suppressive effect of BMSCs on the Th17 cell function is involved in adenosine production.

 

Figure1ABC

Figure1DE

Figure 1. The suppressive effect of MSCs on the secretion of both IFNg and IL17 by Th17 cells was significant, which was significantly reduced by anti-CD39 treatment(A~C). The reductions of IL-17A and IFNg were shown in MSCs-cocultured supernatents by ELISA, which were significantly reversed by anti-CD39 treatment (D and E). M indicates MSCs, T indicates Th17 cells, and aCD39 presents anti-CD 39 treatment.

 

Figure2A

Figure2BCDE

Figure 2. The inhibitory effect of either 1-D/L MT (inhibitor of IDO) or 1400w dihydrochloride (inhibitor of NOS2) on the suppressive function of MSCs to the secretion of IFNg/IL17 secretion in Th 17 cells, which was less than the blocking effect of anti-CD39 treatment. M indicates MSCs, T indicates Th17 cells, and aCD39 presents anti-CD39 treatment.

 

Significance

Our results demonstrate that the suppressive effect of hBMSCs on the IFN-γ and IL-17A secretion by Th17 cells in a CD39-dependent manner. Moreover, this reduction effect of hBMSCs via CD39 was comparable to or greater than the suppressive effect of BMSCs in the IDO- or NOS2 -dependent pathway. Given that ocular autoimmune disease is known to be involved in Th17 cells-associated inflammation, topical application of hMSCs may be safer and effective option in ocular autoimmune disease through CD39-CD73 dependent pathway considering that direct contact to the target site is possible.

 

Acknowledgments: This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MEST). (NRF 2010-0010629 and NRF 2011-0004128)

 

References

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  2. Saldanha-Araujo F, Ferreira F, Palma P, Araujo A, Queiroz R, et al. (2011) Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes. Stem Cell Res 7: 66-74.
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