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.

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

“…Tim-3, as an important immune regulatory molecule, is expressed on effector Th1 cells and Tc1 cells (8)(9)(10)(11)(12)(13)(14), both of which play important roles in the immune response to HBV. However, whether Tim-3 plays a role in the development of HBV infection still remains unclear.…”

“…As a ligand for Tim-3, galectin-9 is widely distributed in various tissues and is particularly abundant in the liver (29). Previous studies have shown that Tim-3-galectin-9 pathway modulates T cell secretion of IFN- (9,13,14), which is of particular importance to immunity against viral infection. Consistent with these reports, our data verified the simultaneous staining of Tim-3 and IFN- in CD8 + T cells ( Figures 2 and 4), which might explain why Tim-3 pathway influences IFN- production from CD8 + T cells.…”

“…In Tim-3 shRNA-1-treated HBV model mice, Tim-3 up-regulation was reversed on hepatic CD8 + T cells comparable to control mice on day 10, while unrelated shRNA (unshRNA) had no such effects (Tim-3 shRNA-1 vs unshRNA, p < 0.05; Tim-3 shRNA-1 vs control, p > 0.05) (Figures 4A and 4B). Previous studies have shown that Tim-3-galectin-9 pathway modulates T cell secretion of IFN- (9,13,14), which is of particular importance to immunity against viral infection. Consistent with this, our results showed that Tim-3 knockdown in vivo significantly decreased the percent of Tim-3 expressing cells in IFN--producing CD8 + T cells (Tim-3 shRNA-1 vs unshRNA, p < 0.05; Tim-3 shRNA-1 vs control, p > 0.05) (Figures 4C and 4D) and increased IFN- expression on hepatic CD8 + T cells (Tim-3 shRNA-1 vs unshRNA, p < 0.05) (Figures 4E and 4F).…”

“…The administration of anti-Tim-3 mAbs augmented the activation of effector T cells expressing IFN-. So far, evidence has been provided for an important role of Tim-3 in a range of diseases, including inflammatory diseases (14)(15)(16)(17)(18)(19). However, no study has been reported on the role of Tim-3 in immune repression during HBV infection.…”

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

“…Activation of Tim3 inhibits the activity of Th1 cells and production of IFN-c, both of which play important roles in antitumor immunity [7,8]. Tim3, a transmembrane protein that contains an immunoglobulin-and a mucin-like domain, is expressed on many cells including Th1 cells, CD8 T-cells, monocytes, and dendritic cells [9][10][11][12]. Interaction of Tim3 with its ligands, phosphatidylserine and galectin-9, modulates the function of these cells [13,14].…”