Project 460069

Every tissue must be able to respond to potentially dangerous infections, such as novel coronavirus, HIV, and many others, all while maintaining or returning to a state of "homeostasis" - a steady state that establishes normal functions like breathing and reproduction, while remaining resilient to external stimuli that could disrupt this state and cause inflammation. Inflammation, while required to mount effective host immune responses, can cause damage to host if excessive or prolonged. Our research group has shown that inflammation in the vagina, as defined by increased levels of communication proteins called cytokines, can predict women who are at increased risk of becoming HIV infected if exposed. Inflammation is also higher in women who experience reproductive health complications. Therefore, limiting inflammation to within normal boundaries might be a way to improve women's health. Because inflammation can be caused by many types of stimuli, another approach to targeting inflammation is by employing host mechanisms that naturally control inflammation. This grant focuses on a type of immune cell called a regulatory T cell, or Treg, whose role it is in tissues to constrain excessive immune responses that can cause damage to the host. We have shown in a small pilot study that women with more Treg in their vagina have less inflammation. In this proposal we aim to build on this finding in the following three ways. First, we will study Treg from the vagina in more detail, to determine the locations and types of Treg that control inflammation the best, and mechanisms by which this occurs. Next we will study young women from Uganda, to determine if over time, having more vaginal Treg can limit vaginal inflammatory responses. Finally, we will determine if inducing Treg in the vagina of mice can prevent mice from making excessive inflammatory responses. This work aims to find better HIV prevention strategies for women who are at risk of acquiring HIV infection.