Proposed model for role of Galectin-9 and IL-21 during acute HCV infection.

<p>(<b>A</b>) HCV infection of hepatocytes and antigen uptake and presentation by liver-resident and circulating antigen presenting cells (APCS) prime HCV-specific CTLs and helper CD4 T cells including Th1 and Th17 cells. Function and survival of HCV-specific CTLs are sustained by increased production of IL-21 by Th17 cells during the late acute phase of spontaneously resolving HCV infection. (<b>B</b>) In patients with chronic evolution, multiple inhibitory mechanisms cooperate to induce failure of the immune response and facilitate viral persistence. (1) HCV-specific Th17 cells produce less IL-21 thus compromising CTL survival and function. (2) HCV-specific CTLs become exhausted and up-regulate exhaustion molecules like Tim-3, PD-1 and CTLA-4 and become more susceptible to apoptosis that is aggravated by lack of sufficient IL-21. (3) CD39<b>⁺</b> Tregs are increased in frequency and may directly inhibit Th17 cells and Tim-3-expressing CTLs via Gal-9-mediated apoptosis or through classical mechanisms including cellular contact and immuno-modulatory cytokines like IL-10 and TGF-β.