Regulatory T cell coordination of the mucosal NK cell response during viral infection - PROJECT SUMMARY We continue to lack vaccines for many pathogens of public health importance, including herpes simplex virus-2 (HSV-2), human immunodeficiency virus-1 (HIV-1), and tuberculosis (TB). In many infections of public health importance including HSV-2, the mucosal barrier is the portal of pathogen exposure, yet the regulation of mucosal immunity is incompletely understood. The broad objective of this proposal is to achieve a more in-depth knowledge of the regulation of mucosal immunity in the anti-pathogen immune response. Nature killer (NK) cells at mucosal sites are critical in controlling infections. NK cells are important for resolving HSV-2 infection by producing cytokines early after infection that activate adaptive immune responses, such as IFNg. Although NK cells are part of the innate immune system, there is evidence suggesting that NK cells can become long-lived memory-like cells and play an important role in secondary immune responses. NK cells remain functionally primed in the mucosal tissue up to 30 days after HSV-2 infection. During HSV-2 infection, NK cell activation is driven by inflammatory cytokines, and therefore must be subject to immune regulation to limit immunopathology. Regulatory T cells (Tregs) act by suppressing immunity and are crucial to maintaining peripheral tolerance and limiting tissue damage from excess inflammation. In the context of infection, there is evidence that Tregs unexpectedly also play a pivotal role in orchestrating an anti-pathogen response. Tregs are necessary during early HSV-2 infection to coordinate a productive anti-viral immune response in the vaginal tract (VT) in mice. However, the mechanism by which Tregs coordinate early antiviral innate immunity while limiting immunopathology remains poorly defined. While the link between NK cells and Tregs during infection is not well understood, there is evidence that the NK cell response is altered by the absence of Tregs. We previously published that Tregs are required for the proper homing of NK cells to the VT after HSV-2 infection. More recently, I have generated data that Treg depletion during HSV-2 infection increases NK cell maturation providing evidence that Tregs act in limiting NK cell response during viral infection. Thus, our rigorous prior research suggests a dual function for Tregs in modulating NK cell responses in which Tregs are required for both coordination of NK cell response and limiting excessive inflammation. However, the mechanisms and timing by which Tregs modulate NK cells within mucosal tissues during infection remain to be studied. This proposed work is essential for understanding the role of Tregs in coordinating and regulating NK cell function in mucosal tissues during viral infection. This understanding of mucosal immunology will be crucial to informing vaccine strategies to develop a balanced, robust, and tissue-specific immune response against viral infections, while still limiting immunopathology.
