Human placental mesenchymal stromal cells modulate IFN-γ and IL-10 secretion by CD4+T cells via CD73, and alleviate intestinal damage in mice with graft-versus-host disease

Background: Intestinal inflammatory damage is an important factor in the development of graft-versus-host disease (GVHD). IFN-gamma and IL-10 play key roles in gastrointestinal inflammation, and human placental mesenchymal stromal cells (hPMSCs) can alleviate inflammatory damage during GVHD. CD73 is highly expressed by hPMSCs. We aimed to study whether hPMSCs could alleviate intestinal damage in GVHD mice by modulating IFN-gamma and IL-10 in CD4(+)T cells by CD73. Methods: A GVHD mouse model was induced using 8-week-old C57BL/6J and BALB/c mice, which were treated with regular hPMSCs (hPMSCs) or hPMSCs expressing low level of CD73 (shCD73). Then, the levels of IFN-gamma and IL-10 in CD4(+)T cells were determined using flow cytometry. Transmission electron microscopy, western blotting, and morphological staining were employed to observe the intestinal damage. Results: hPMSCs ameliorated pathological damage and inhibited the reduction of the tight junction molecules occludin and ZO-1. They also downregulated IFN-gamma and upregulated IL-10 secretion in CD4(+)T cells via CD73. Moreover, IL-10 mitigated the inhibitory effects of IFN-gamma on the expression of occludin in both Caco-2 and NCM460 cells in vitro, but did not affect ZO-1. In addition, hPMSCs upregulated the level of AMPK phosphorylation in CD4(+)T cells by CD73, which is positively associated with the proportion of CD4(+)IFN-gamma+IL-10(+)T, and CD4(+)IFN-gamma-IL-10(+)T cells. Conclusions: Our findings suggested that hPMSCs may balance the levels of IFN-gamma and IL-10 in CD4(+)T cells by promoting the phosphorylation of AMPK via CD73, which alleviates the loss of occludin and ZO-1 in intestinal epithelial cells and, in turn, reduces inflammatory injury in GVHD mice.