Exopolysaccharide from a commensal bacterium improves outcome of graft versus host disease by decreasing donor T cell activation

Abstract

Abstract We previously showed that exopolysaccharide (EPS) produced by a commensal bacterium, Bacillus subtilis, induces alternatively-activated, anti-inflammatory M2 macrophages that protect mice from T cell-dependent inflammatory disease, induced by the enteric pathogen Citrobacter rodentium. Here, we show that EPS induces clinical improvement in another T cell-mediated disease, graft versus host disease (GVHD). GVHD is a common complication of allogenic bone marrow transplantation and is caused by the activation of alloreactive donor T cells. To monitor the inflammatory response of allogeneic bone marrow cells in recipient mice, we used donor cells from transgenic mice that express a luciferase-based biosensor that is cleaved by caspase-1, a protein activated during inflammation. We found that donor inflammatory responses and T cell activation was decreased in EPS-treated mice. Our previous data indicate that EPS does not have a direct effect on T cells. To identify the cell type affected by EPS, we tested the activity of EPS on bone marrow-derived dendritic cells (BMDCs) and found that these cells have upregulated expression of the inhibitory molecule, PD-L1, and the cells inhibited alloreactive T cell activation and proliferation in mixed lymphocyte reactions (MLR). We also found that in vivo injection of EPS resulted in the upregulation of PD-L1 expression on splenic dendritic cells. We conclude that EPS ameliorates clinical manifestations of GVHD by decreasing the activation of donor T cells, and we suggest that EPS affects T cells by inducing inhibitory dendritic cells.