Fig. 7. A model for Tim-3/Gal-9 interactions in regulating the HCV-mediated imbalance of Foxp3⁺ Tregs/Foxp3⁻ Teffs during HCV infection.

Our data support the proposed notion that HCV infection up-regulates the expression of Tim-3 and accumulation of Foxp3⁺ Tregs, inhibiting Foxp3⁻ Teff responses and resulting in blunted antiviral T cell responses with decreased pro-inflammatory cytokines and increased anti-inflammatory cytokines that contribute to viral persistence. Specifically, HCV-mediated Tim-3 inhibit proliferation and induce apoptosis of activated CD25⁺Foxp3⁻ Teffs, leading to impaired protective Th1 responses as well as limited pathogenic injury. Meanwhile, as a negative feedback mechanism, Tim-3 is also up-regulated and tempers CD25⁺Foxp3⁺ Tregs, which accumulate during HCV infection and may further dampen antiviral T cell responses. Notably, Tim-3 pathway fine-tunes the development and function of Foxp3⁺ Tregs and blocking Tim-3 signaling may correct the imbalance of Foxp3⁺ Tregs/Foxp3⁻ Teffs established during HCV infection. Therefore, the counter-regulatory effect of Tim-3 on Tregs should be taken into account when manipulating this inhibitory pathway as a novel strategy for immunotherapy against chronic viral infection, so as to balance the protective immune responses and avoid T cell-dependent injury.