Galectin-9 and IL-21 Mediate Cross-regulation between Th17 and Treg Cells during Acute Hepatitis C

Loss of cd4 t cell help correlates with virus persistence during acute hepatitis c virus (hcv) infection,but the underlying mechanism(s) remain unknown. we developed a combined proliferation/intracellular cytokine staining assay to monitor expansion of hcv-specific cd4 t cells and helper cytokines expression patterns during acute infections with different outcomes. we demonstrate that acute resolving hcv is characterized by strong th1/th17 responses with specific expansion of il-21-producing cd4 t cells and increased il-21 levels in plasma. in contrast,viral persistence was associated with lower frequencies of il-21-producing cd4 t cells,reduced proliferation and increased expression of the inhibitory receptors t cell immunoglobulin and mucin-domain-containing-molecule-3 (tim-3),programmed death 1 (pd-1) and cytotoxic t-lymphocyte antigen 4 (ctla-4) on hcv-specific cd8 t cells. progression to persistent infection was accompanied by increased plasma levels of the tim-3 ligand galectin-9 (gal-9) and expansion of gal-9 expressing regulatory t cells (tregs). in vitro supplementation of tim-3high hcv-specific cd8 t cells with il-21 enhanced their proliferation and prevented gal-9 induced apoptosis. sirna-mediated knockdown of gal-9 in treg cells rescued il-21 production by hcv-specific cd4 t cells. we propose that failure of cd4 t cell help during acute hcv is partially due to an imbalance between th17 and treg cells whereby exhaustion of both cd4 and cd8 t cells through the tim-3/gal-9 pathway may be limited by il-21 producing th17 cells or enhanced by gal-9 producing tregs. © 2013 kared et al.