The impact of exogenous polyamines on cervicovaginal T cell immunity

About This Grant

Project Summary/Abstract The cervicovaginal mucosa is a critical immunological interface balancing protection against pathogens with tolerance to commensal microbes and semen. Cervicovaginal T cells are essential for viral defense, such as against herpes simplex virus type 2 (HSV-2), which infects half a billion people worldwide and persists at the vaginal mucosa. However, the metabolic factors shaping cervicovaginal T cell function remain poorly understood, creating a critical need to define how local metabolites influence mucosal immunity and infection susceptibility. In the gut mucosa, microbial and diet-derived polyamines exert strongly immunosuppressive effects by promoting the expansion of regulatory T cells (Tregs) and inhibiting the activation of pro-inflammatory immune cells. Similarly, in the tumor microenvironment, polyamines produced by tumor cells inhibit the function of effector T cells. It is unknown how exogenous polyamines modulate cervicovaginal mucosal immunity and susceptibility to infection. Notably, the cervicovaginal mucosa is exposed to much higher levels of exogenous polyamines compared to gut, primarily through seminal fluid, which is rich in spermine and spermidine, and bacteria associated with bacterial vaginosis, which produce putrescine. Recent evidence suggests that the catabolism of high levels of exogenous polyamines induces oxidative stress and mitochondrial damage, which may contribute to polyamine-mediated immunosuppression. We have recently found that exogenous polyamines at physiologically relevant concentrations are taken up by circulating T cells, suppress T cell activation and proliferation, and decrease mitochondrial membrane potential. Thus, we hypothesize that exogenous polyamines suppress cervicovaginal T cell activation and function by inducing metabolic dysfunction, thereby creating an immune-tolerant environment that increases HSV-2 infection susceptibility. To test this, Aim 1 will determine how exogenous polyamines influence cervicovaginal T cell activation, proliferation, cytokine production, and metabolism in vitro. Aim 2 will examine the effects of exogenous polyamines on cervicovaginal immunity and HSV-2 infection susceptibility in vivo. By defining how microbial and seminal metabolites regulate cervicovaginal mucosal immunity, this work will provide novel insights into immune- metabolic interactions in the female genital tract and may reveal new therapeutic targets for STI prevention, improving reproductive health outcomes, and optimizing mucosal vaccine efficacy. To carry out these aims, the PI has assembled a team at Harvard Medical School and the Ragon Institute with combined expertise on mucosal immunology, immunometabolism, and infectious disease who will collaborate and support the PI’s development as an aspiring physician scientist and leader in mucosal immunology.