Nk Cells Require Antigen-Specific Memory Cd4(+) T Cells To Mediate Superior Effector Functions During Hsv-2 Recall Responses In Vitro

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 gamma (IFN-gamma) upon re-exposure to HSV-2 antigens in a mouse model of genital HSV-2 immunization. We find that naive NK cells do not require any prior stimulation or priming to be activated to produce IFN-gamma. 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-gamma