NK cells require antigen‐specific memory CD4+ T cells to mediate superior effector functions during HSV‐2 recall responses in vitro

Cross‐talk between HSV‐2‐specific CD4+ T cell and NK cells impacts NK cell function during secondary exposure to HSV‐2 antigens. Natural killer (NK) cells have an important role in mounting protective innate responses against genital herpes simplex virus type 2 (HSV‐2) infections. However their role as effectors in adaptive immune responses against HSV‐2 is unclear. Here, we demonstrate that NK cells from C57BL/6 mice in an ex vivo splenocyte culture produce significantly more interferon γ (IFN‐γ) upon re‐exposure to HSV‐2 antigens in a mouse model of genital HSV‐2 immunization. We find that naïve NK cells do not require any prior stimulation or priming to be activated to produce IFN‐γ. Our results demonstrate that HSV‐2–experienced CD4+ T cells have a crucial role in coordinating NK cell activation and that their presence during HSV‐2 antigen presentation is required to activate NK cells in this model of secondary immune response. We also examined the requirement of cell‐to‐cell contacts for both CD4+ T cells and NK cells. NK cells are dependent on direct interactions with other HSV‐2–experienced splenocytes, and CD4+ T cells need to be in close proximity to NK cells to activate them. This study revealed that NK cells do not exhibit any memory toward HSV‐2 antigens and, in fact, require specific interactions with HSV‐2–experienced CD4+ T cells to produce IFN‐γ