The Fifth Epidermal Growth Factor-like Region of Thrombomodulin Alleviates Murine Graft-versus-Host Disease in a G-Protein Coupled Receptor 15 Dependent Manner

•TME5 alleviated murine aGVHD in vivo and suppressed allo-reaction in vitro.•TME5 inhibited IL-6 production and facilitated differentiation of induced Tregs.•TME5 reduced activation of bone marrow derived dendritic cells.•GPR15 mediated the anti-inflammatory effects of TME5 in allo-reaction.

Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor-like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow-derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT.