CD8 T cells are crucial for humoral immunity establishment by SA14-14-2 live attenuated Japanese encephalitis vaccine in mice.

The live attenuated SA14-14-2 Japanese encephalitis (JE) vaccine is a historical vaccine that protects against JE. Despite its extensive use, the mechanism of protective immunity conferred by the SA14-14-2 vaccine is not well established. Here, we used mouse models to understand the mechanism of the development of humoral immunity against the vaccine. The vaccine induces robust GC responses within a week postimmunization. In lethal virus challenge, we show that CD4 T cells alone, but not CD8 T cells, are sufficient to confer vaccine-mediated protection. However, the CD4-mediated protection was potentiated in the presence of vaccine-primed CD8 T cells. Employing CD8-deficient mice, we show that both the protective traits of CD4 T cells and the quality of antibody response to the vaccine are impaired in absence of CD8 T cells. We further demonstrate that the poor protective immune response induced by the vaccine in absence of CD8 T cells is mainly due to the impaired differentiation and function of follicular Th cells, leading to suboptimal GC reaction. Our study highlights an unprecedented role of CD8 T cells in the establishment of humoral responses to the vaccine. By elucidating underlying cellular determinants of vaccine-induced protective immunity, our work has implications for rational design of vaccines against JE virus and related flaviviruses.