The DC ‐ HIL ligand syndecan‐4 is a negative regulator of T‐cell allo‐reactivity responsible for graft‐versus‐host disease

Summary Acute graft‐versus‐host disease ( GVHD ) is the most important cause of mortality after allogeneic haematopoietic stem cell transplantation. Allo‐reactive T cells are the major mediators of GVHD and the process is regulated by positive and negative regulators on antigen‐presenting cells ( APC ). Because the significance of negative regulators in GVHD pathogenesis is not fully understood, and having discovered that syndecan‐4 ( SD ‐4) on effector T cells mediates the inhibitory function of DC ‐ HIL on APC , we proposed that SD ‐4 negatively regulates the T ‐cell response to allo‐stimulation in acute GVHD , using SD ‐4 knockout mice. Although not different from their wild‐type counterparts in responsiveness to anti‐ CD 3 stimulation, SD ‐4 −/− T cells lost the capacity to mediate the inhibitory function of DC ‐ HIL and were hyper‐reactive to allogeneic APC . Moreover, infusion of SD ‐4 −/− T cells into sub‐lethally γ‐irradiated allogeneic mice worsened mortality, with hyper‐proliferation of infused T cells in recipients. Although there my be little or no involvement of regulatory T cells in this model because SD ‐4 deletion had no deleterious effect on T ‐cell‐suppressive activity compared with SD ‐4 +/+ regulatory T cells. We conclude that SD ‐4, as the T ‐cell ligand of DC ‐ HIL , is a potent inhibitor of allo‐reactive T cells responsible for GVHD and a potentially useful target for treating this disease.