IL-27 Promotes Human Placenta–Derived Mesenchymal Stromal Cell Ability To Induce the Generation of CD4+IL-10+IFN-γ+ T Cells via the JAK/STAT Pathway in the Treatment of Experimental Graft-versus-Host Disease

Abstract

Human mesenchymal stromal cells (MSCs) harbor immunomodulatory properties to induce the generation of suppressive T cells. MSCs have been successfully used in treating graft-versus-host disease (GVHD) accompanied by abundant inflammatory cytokines such as IL-27. This study investigated the effects of IL-27 on the human placenta-derived MSCs (hPMSCs) to induce generation of CD4⁺IL-10⁺IFN-γ⁺ T cells in vitro and in the humanized xenogenic GVHD NOD/SCID model. The results showed that the percentages of CD4⁺IL-10⁺IFN-γ⁺ T cells were significantly increased in activated human PBMC from both healthy donors and GVHD patients with hPMSCs and in the liver and spleen of hPMSC-treated GVHD mice, and the level of CD4⁺IL-10⁺IFN-γ⁺ T cells in the liver was greater than that in the spleen in hPMSC-treated GVHD mice. The serum level of IL-27 decreased and the symptoms abated in hPMSC-treated GVHD. Further, in vitro results showed that IL-27 promoted the regulatory effects of hPMSCs by enhancing the generation of CD4⁺IL-10⁺IFN-γ⁺ T cells from activated PBMC. Activation occurred through increases in the expression of programmed death ligand 2 (PDL2) in hPMSCs via the JAK/STAT signaling pathway. These findings indicated that hPMSCs could alleviate GVHD mice symptoms by upregulating the production of CD4⁺IL-10⁺IFN-γ⁺ T cells in the spleen and liver and downregulating serum levels of IL-27. In turn, the ability of hPMSCs to induce the generation of CD4⁺IL-10⁺IFN-γ⁺ T cells could be promoted by IL-27 through increases in PDL2 expression in hPMSCs. The results of this study will be of benefit for the application of hPMSCs in clinical trials.