Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

Abstract

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

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). The administration of anti-Tim-3 mAbs augmented the activation of effector T cells expressing IFN-.…”

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…Exhausted T cells have also been identified in different viral infections, such as HIV and hepatitis A and B virus (Sharpe et al ., 2007; Keir et al ., 2008). Several previous studies of LCMV, HIV, and HCV infections have suggested that Tim‐3 is another inhibitory marker of exhausted T cells (Jones et al ., 2008; Golden‐Mason et al ., 2009; Jin et al .,2010). Tim‐3 was initially identified in IFN‐γ‐secreting Th1 cells and CD8 + T cytotoxic type 1 (Tc1) cells (Monney et al ., 2002).…”