Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance

Abstract

T helper type 1 (T(H)1) immune responses are central in cell-mediated immunity, and a T(H)1-specific cell surface molecule called Tim-3 (T cell immunoglobulin domain, mucin domain) has been identified. Here we report the identification of a secreted form of Tim-3 that contains only the immunoglobulin (Ig) variable (V) domain of the full-length molecule. Fusion proteins (Tim-3-Ig) of both Tim-3 isoforms specifically bound CD4(+) T cells, indicating that a Tim-3 ligand is expressed on CD4(+) T cells. Administration of Tim-3-Ig to immunized mice caused hyperproliferation of T(H)1 cells and T(H)1 cytokine release. Tim-3-Ig also abrogated tolerance induction in T(H)1 cells, and Tim-3-deficient mice were refractory to the induction of high-dose tolerance. These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector T(H)1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance.

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

“…Tim-3 has been proposed to be a novel candidate target for the treatment of SLE. [32][33][34][35][36][37] Unlike the other Tim molecules, Tim-4 is exclusively expressed in APCs and it is unclear to date whether Tim-4 plays a role in SLE pathogenesis. Due to the lack of a directly labeled anti-human Tim-4 antibody, it is difficult to quantitate Tim-4 protein on APCs by flow cytometry.…”

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).…”

“…Tim-3 ligation negatively regulates Th1 responses and influences the ability to induce tolerance in both mice and humans (9)(10)(11)(12). Recently, it was reported that Tim-3 was up-regulated on effector CD8 + T cells in chronic virus infection (13).…”