In this study, we provided, for the first time, that HTNV could induce both Th1 and ThGzmB+ cell responses involving in the defense against HTNV infection; we showed that HTNV-Gn/Gc-specific CD4+T-cell immunity with broad reactivity, polyfunctionality, expansion capacity, and effector phenotype, inversely correlated with plasma viral load and the HFRS disease outcome; we further provided evidence that HTNV-Gn/Gc-specific CD4+T cells mediated host defense against HTNV infection maybe through the Th1 induced antiviral condition of the host cells and the cytotoxic effect of ThGzmB+ cells. Here, CD4 is linked to hemorrhagic fever with renal syndrome.