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. 2019 Mar 15;11(3):1299-1310.
eCollection 2019.

CD150 high Treg Cells May Attenuate Graft Versus Host Disease and Intestinal Cell Apoptosis After Hematopoietic Stem Cell Transplantation

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Free PMC article

CD150 high Treg Cells May Attenuate Graft Versus Host Disease and Intestinal Cell Apoptosis After Hematopoietic Stem Cell Transplantation

Sainan Yang et al. Am J Transl Res. .
Free PMC article

Abstract

Combined transplantation of regulatory T cells (Treg cells) may significantly attenuate graft versus host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Recent studies indicated that CD150+Treg cells could secret adenosine to maintain the quiescent status of HSCs. However, whether it is attributable to the attenuation of GVHD after HSCT is still unclear. In vitro studies revealed that CD150+Treg cells induced immune tolerance was comparable to that induced by CD150-Treg cells, but CD150+Treg cells can secret more adenosine, increase P-AMPK expression and regulate energy metabolism to induce the proliferation of HSC proliferation and inhibit their differentiation into dendritic cells. In this study, GVHD animal model was established, and combined transplantation of Treg cells and HSCs was performed. Results showed the survival time was significantly prolonged, the proliferation rate of HSCs increased significantly and the proportion of undifferentiated HSCs elevated significantly after CD150+Treg transplantation as compared to CD150-Treg transplantation. Immunohistochemistry revealed CD150+Treg cells could secret adenosine, activate AMPK expression and inhibit intestinal cell apoptosis and inflammation after HSCT. Taken together, this study indicates CD150+Treg cells can regulate energy metabolism to attenuate GVHD and intestinal cell apoptosis after HSCT.

Keywords: CD150; Regulatory T cells; energy metabolism; graft versus host disease; hematopoietic stem cell transplantation.

Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Adenosine concentration of CD150-Treg cells and CD150+Treg cells. Flow cytometry showed the expression of HLA-G and CTLA-4 was comparable between CD150-Treg and CD150+Treg cells. ELISA revealed the concentration of IL-10 and TGF-β in the supernatant was similar between CD150-Treg and CD150+Treg cells. The adenosine concentration in CD150+Treg cells was about 2.66 times that in CD150-Treg cells.
Figure 2
Figure 2
CD150+Treg cells promote HSCs proliferation. EDU proliferation test showed the proliferation rate was significantly different between control group and CD150-Treg group. In CD150+Treg group, the proliferation rate was significantly higher than CD150-Treg group. Adenosine inhibition could significantly reduce the HSCs proliferation induced by CD150+Treg cells.
Figure 3
Figure 3
CD150+Treg cells inhibit HSCs differentiation. Flow cytometry showed the proportion of DCs cells differentiated from HSCs in control group was significantly different from IL-6 group. The proportion in CD150+Treg group was significantly lower than Il-6 group. Adenosine could significantly reverse the CD150+Treg cells induced inhibition of HSCs differentiation.
Figure 4
Figure 4
CD150+Treg cells elevate energy metabolism of HSCs. MMP and intracellular ATP concentration were comparable between CD150-Treg group and control group. MMP and intracellular ATP concentration were significantly different from those in CD150-Treg group. Adenosine inhibition could significantly reduce the CD150+Treg cells induced increase in energy metabolism of HSCs. Immunohistochemistry showed CD150+Treg cells could significantly increase the p-AMPK expression in HSCs, which however was attenuated by adenosine inhibition. Correlation analysis revealed that p-AMPK expression was positively related to the Ki-67 proliferation index. These findings indicate that CD150+Treg cells can secret adenosine to activate AMPK and increase energy metabolism, which elevates the proliferation of HSCs.
Figure 5
Figure 5
CD150+Treg cells promote HSCs proliferation and inhibit their differentiation in vivo. The proportion of DiI+CD34- differentiated cells was significantly different between control group and CD150-Treg group. This proportion in CD150+Treg group was significantly lower than CD150-Treg group. Adenosine inhibition or AMPK inhibition significantly reduced the proportion of differentiated cells as compared to CD150+Treg group.
Figure 6
Figure 6
CD150+Treg cells can secret adenosine to activate AMPK expression and regulate energy metabolism, attenuating the intestinal injury and inflammation after HSCs transplantation. Intestinal injury was significantly attenuated in CD150-Treg group and the number of infiltrated LCA+ lymphocytes reduced significantly as compared to control group. In CD150+Treg group, the number of infiltrated LCA+ lymphocytes reduced significantly by 63% as compared to CD150-Treg group.
Figure 7
Figure 7
CD39 and CD73 mRNA expression. CD39 and CD73 mRNA expression in CD150+Treg cell were significantly higher than CD150-Treg cell, indicating that CD39-CD73-adenosine signaling pathway was involved in biofunction of CD150+Treg cell.
Figure 8
Figure 8
CD39 and CD73 protein expression. CD39 and CD73 protein expression in CD150+Treg cell was significantly higher than CD150-Treg cell, which confirmed the above results.
Figure 9
Figure 9
CD150highTreg cell transplantation attenuates graft versus host disease after hematopoietic stem cell transplantation. CD150+Treg cells can regulate energy metabolism to inhibit the GVHD and intestinal cell apoptosis secondary to HSCs transplantation.

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