Tim-3 Pathway Controls Regulatory and Effector T Cell Balance during Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Up-regulation of inhibitory signaling pathways (such as Tim-3) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. While the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3+ Tregs is poorly explored. In this pilot study, we investigated whether and how the Tim-3 pathway alters Foxp3+ Treg development and function in patients with chronic HCV infection. We found that Tim-3 was up-regulated, not only on IL-2-producing CD4+CD25+Foxp3− Teffs, but also on CD4+CD25+Foxp3+ Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared to healthy subjects. Tim-3 expression on Foxp3+ Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but inversely associated with proliferation of IL-2-producing Teffs. Moreover, Foxp3+ Tregs were found to be more resistant to, and Foxp3− Teffs more sensitive to, TCR-activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4+CD25+ T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3+ Tregs/Foxp3− Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control regulatory and effector T cell balance through altering cell proliferation and apoptosis during HCV infection.

Induction, control, and plasticity of Treg cells: The immune regulatory network revised?

“…Then, Tim-3 expression is significantly upregulated on iTreg cells and deliver a negative signal tempering Treg expansion and function: blocking Tim-3/Gal-9 ligation further increased the expansion and TGF-β/IL-10 production by Treg cells in the presence of Gal-9 + HCV + Huh-7 cells. These data are consistent with previous evidence showing that both Tim-3 and PD-1, together with the simultaneous TCR/MHC-peptide interaction, negatively regulate the expansion and suppressive function of Treg cells by controlling STAT-5 phosphorylation, at the site of inflammation in chronic HCV infection [17,18]. Therefore, Tim-3, as well as PD-1 [16,17], seem to act as a double-edged sword with the effect dependent on the phase of T cell activation: both Tim-3 and PD-1 can contribute to Treg-cell conversion from naïve Tconv cells, i.e.…”

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

“…These results are in agreement with our previous observations that another negative signaling molecule, T cell immunoglobulin and mucin domain protein 3 (Tim-3), is upregulated on NK cells to dampen their functions, with inhibited activation (CD69), proliferation (Ki69), degranulation (CD107a), and killing activity (granzyme B) following HCV infection (data not shown). This in turn interplays with monocytes and T cells (including Th17 and Foxp3 ϩ Tregs) in immune dysregulation that contribute to viral persistence (42)(43)(48)(49). This also supports the notion that HCV may utilize KLRG1-an intrinsic mercenary of cell feedback regulation-for the purpose of virus persistence and thus facilitate chronic infection.…”

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…TIM-3 binds to its ligand galectin-9, which is expressed on KCs and other myeloid cells, and negatively regulates T-cell response [9]. HCVinfected hepatocytes also express galectin-9 and induce CD4 + CD25 + FOXP3 + Treg infiltration in the diseased liver [45]. Li et al showed that TIM-3 expression is increased in the T lymphocytes infiltrating in HCC [9].…”