Preferential Involvement of Tim-3 in the Regulation of Hepatic CD8⁺ T Cells in Murine Acute Graft-versus-Host Disease

Abstract

Tim-3, a member of the T cell Ig mucin (TIM) family regulates effector Th1 responses. We examined Tim-3 and its ligand expression as well as the effects of anti-Tim-3 mAb treatment in a murine model of acute graft-vs-host disease (aGVHD). In mice with aGVHD, Tim-3 expression was markedly up-regulated on splenic and hepatic CD4⁺ and CD8⁺ T cells, dendritic cells (DCs), and macrophages, and this was especially dramatic in hepatic CD8⁺ T cells. Both donor- and host-derived CD8⁺ T cells induced similar levels of Tim-3. Tim-3 ligand expression was also up-regulated in splenic T cells, DCs, and macrophages, but not in the hepatic lymphocytes. The administration of anti-Tim-3 mAbs accelerated aGVHD, as demonstrated by body weight loss, reduction in total splenocyte number, and infiltration of lymphocytes in the liver. IFN-γ expression by splenic and hepatic CD4⁺ and CD8⁺ T cells was significantly augmented by anti-Tim-3 mAb treatment. In addition, the cytotoxicity against host alloantigen by donor CD8⁺ T cells was enhanced. These results demonstrate that the anti-Tim-3 treatment in aGVHD augmented the activation of effector T cells expressing IFN-γ or exerting cytotoxicity. Our results suggest that Tim-3 may play a crucial role in the regulation of CD8⁺ T cells responsible for the maintenance of hepatic homeostasis and tolerance.