Expansion of genital Tregs reduces neutrophil influx and maintains mucosal barrier integrity during inflammatory bacteria challenge.

Genital inflammation is associated with increased HIV risk. We previously found that endocervical Tregs correlated with decreased genital inflammation and reduced HIV target cells. IL-2 induces Tregs, and efforts to potentiate its regulatory activities clinically are ongoing. In this study, intraperitoneal administration of IL-2 conjugated to IL-2mAb clone JES6-1A12 (IL2C-trimeric) in estrous-synchronized female FoxP3GFP mice selectively expanded Tregs in the lower female genital tract, with limited effects on non-Treg cells. IL2C-trimeric increased the expression of GITR on Tregs, and most Tregs expressed tissue residency markers. IL2C-trimeric pre-treatment prevented neutrophil influx during vaginal challenge with both nonoxynol-9 (N-9) and Mobiluncus mulieris, but maintenance of E-cadherin expression and barrier integrity was only observed for M. mulieris and not N-9. Depletion of FoxP3+Tregs reversed the protective effects of IL2C-trimeric. Thus, induction of Tregs could be a potential strategy to regulate genital inflammation, reduce HIV acquisition risk, and improve reproductive health outcomes in women.