Crosstalk between mucosal Tregs and NK cells: Balance between barrier integrity and pathogen defense 2570

Abstract Description Mucosal immunity in the vaginal tract (VT) remains poorly characterized despite its critical role in protecting from sexually transmitted infections. During infection in the VT, the immune response must balance barrier integrity with host protection. My goal is to define how regulatory T cells (Tregs) and natural killer (NK) cells maintain this balance despite their seemingly opposing functions. I have found that TGFb production by Tregs promotes NK cell quiescence and tissue residency in mucosal tissue. Tregs are an important source of TGFb in the VT as the amount of TGFb found in vaginal washes significantly decreases (p = 0.0292) when Tregs are depleted in naive mice. TGFb can directly limit NK cell effector function. When NK cells are stimulated with cytokines found downstream of infection, IL-12/IL-18, in addition to TGFb, TGFb reduces the frequency of NK cells expressing IFNg (p = 0.0089), GranzymeB (p = 0.0735), and CD69 (p = 0.0005). In addition, TGFb increases CD103 expression on NK cells (p = 0.0046), increasing tissue retention of NK cells in the VT. During HSV-2 infection, TGFb is drastically reduced in vaginal washes 2 days post infection (p = 0.0008) to allow for an enhanced NK cell response. This suggests the NK cells in the VT may be regulated by Tregs to limit tissue damage but are poised to respond robustly to inflammatory stimuli. Altogether, I demonstrate how NK cells and Tregs maintain a critical balance at an important barrier site. Funding Sources Supported by NIH/NIAID K99AI180649 and T32 AI007509 to S.C.V., R01 AI141435 and R01 AI131914 to J.M.L., and R01 AI172111 to J.M.L., M.P. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)