HCV‐infected hepatocytes drive CD4⁺CD25⁺Foxp3⁺ regulatory T‐cell development through the Tim‐3/Gal‐9 pathway

Abstract

Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Accumulation of regulatory T cells (Tregs) and up-regulation of inhibitory signaling pathways (such as Tim-3/Gal-9) play pivotal roles in suppressing antiviral effector T cells (Teffs) that are essential for viral clearance. While Tim-3/Gal-9 interactions have been shown to negatively regulate Teffs, their role in regulating Tregs is poorly understood. To explore how Tim-3/Gal-9 interactions regulate HCV-mediated Treg development, in this study we provide pilot data showing that HCV-infected hepatocytes express higher levels of Gal-9 and TGF-β, and up-regulate Tim-3 expression and regulatory cytokines TGF-β/IL-10 in co-cultured CD4+ T cells, driving conventional CD4+ T cells into CD25+Foxp3+ Tregs. Additionally, recombinant Gal-9 protein can transform TCR-activated CD4+ T cells into Foxp3+ Tregs in a dose-dependent manner. Importantly, blocking Tim-3/Gal-9 ligations abrogates HCV-mediated Treg induction by HCV-infected hepatocytes, suggesting that Tim-3/Gal-9 interactions may regulate Foxp3+ Treg development and function during HCV infection.

Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives TH17 Cell Development during Hepatitis C Virus Infection

“…We have recently demonstrated that HCV not only upregulates Tim-3 expression on activated T cells, but also a Tim-3 ligand, galectin-9 (Gal-9), on the surfaces of infected hepatocytes (37). The HCV-mediated Tim-3/Gal-9 interactions drive naive CD4 ϩ T cells differentiation into CD4…”

“…ϩ CD25 ϩ Foxp3 ϩ T regulatory cells (Tregs) but inhibit CD4 ϩ CD25 ϩ Foxp3 Ϫ T effector cells (Teffs), indicating an immunomodulatory role of HCV-infected hepatocytes (37,38). We show here that HCV also promotes TLR-mediated STAT3 signaling within the virally infected microenvironment and induces a heterodimeric cytokine, IL-23, while inhibiting its counterpart cytokine, IL-12, thereby shifting the balance of antiviral immunity toward a condition favoring viral persistence and autoimmunity.…”

“…We and others have shown that HCV-induced negative signaling molecules, including program death-1 (PD-1), suppressor of cytokine signaling-1 (SOCS-1), and Tim-3, play pivotal role in inhibiting several intracellular signaling pathways, including MAPK, Jak/STAT, and Akt/PI3K, and lead to the inhibition of monocyte IL-12 production, the suppression of virusspecific T cell responses, the promotion of B cell activation and proliferation, and the induction of CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells during HCV infection (20,21,37,38,43). Notably, it has been reported that HCV-specific T H 17 cells were suppressed by production of anti-inflammatory cytokines IL-10 and transforming growth factor ␤ (TGF-␤) (44).…”

Role of Tim-3 in hepatitis B virus infection: An overview

“…Tim-3 + Tregs tend to resist apoptotic signals and show a higher capacity to proliferate, leading to Treg accumulation. Moreover, Ji et al [40] have reported that HCV infection leads to elevated Gal-9 and TGF-β production in hepatocytes.…”

“…Co-culture of HCV-infected hepatocytes and CD4 + T cells induces increased Tim-3 expression on CD4 + T cells, and the Tim-3/Gal-9 interaction enhances TGF-β/ IL-10 production by CD4 + T cells, which accelerates the differentiation of CD4 + T cells into Tregs [40] . However, the regulatory effects of Tim-3 on Tregs in HBV infection remain to be clarified.…”