Myeloid-Derived Suppressor Cells Induce Exhaustion-Like CD8⁺ T Cells during JEV Infection

Japanese encephalitis (JE), caused by Japanese encephalitis virus (JEV), is a mosquito-borne zoonotic disease and a leading cause of viral encephalitis worldwide. While JEV has the ability to traverse the blood-brain barrier (BBB), the precise mechanisms by which it inhibits the immune response prior to penetrating the BBB remain unclear, presenting obstacles in the development of efficacious therapeutic interventions. This study investigated the impact of JEV on CD8⁺ T cell responses, with a particular focus on the dysfunction of CD8⁺ T cells during JEV infection. Our results demonstrated that JEV infection significantly elevated the expression of PD-1 and TIM-3 on CD8⁺ T cells, which are markers of T cell exhaustion, leading to inhibited function and impaired differentiation, resulting in a poorer prognosis in mice. Compared with nondiseased mice, symptomatic mice presented a greater proportion of exhaustion-like CD8⁺ T cells. <i>In vitro</i> experiments further demonstrated that MDSCs induced an exhaustion-like state in CD8⁺ T cells, characterized by significant upregulation of PD-1 and TIM-3 expression. Notably, blocking TIM-3 or depleting MDSCs restored CD8⁺ T cell functionality by rescuing the expression of IFN-γ and TNF-α. Furthermore, the depletion of MDSCs not only alleviated T cell exhaustion-like phenotypes but also improved survival rates in JEV-infected mice. These findings suggest that JEV promotes immune evasion through MDSC-induced CD8⁺ T cell exhaustion-like states and identify TIM-3 as a promising therapeutic target for JE treatment.