Abstract
Regulatory T cells (Tregs) play important roles in tissue homeostasis, but few studies have investigated tissue Tregs in the context of genital inflammation, HIV target cell density, and vaginal microbiota in humans. In women from Nairobi (n=64), the proportion of CD4+ CD25+ CD127low Tregs in the endocervix correlated with those in blood (r=0.31, p=0.01), with a higher Treg frequency observed in the endocervix (median 3.8 vs 2.0%, p<0.0001). Most Tregs expressed FOXP3 in both compartments, and CTLA-4 expression was higher on endocervical Tregs compared to blood (median 50.8 vs 6.0%, p<0.0001). More than half (34/62, 55%) of participants displayed a non-Lactobacillus dominant vaginal microbiota, which was not associated with endocervical Tregs or CD4+ T cell abundance. In a multivariable linear regression, endocervical Treg proportions were inversely associated with the number of elevated pro-inflammatory cytokines (p=0.03). Inverse Treg associations were also observed for specific cytokines including IL-1β, G-CSF, Eotaxin, IL-1RA, IL-8, and MIP-1 β. Higher endocervical Treg proportions were associated with lower abundance of endocervical CD4+ T cells (0.30 log10 CD4+ T cells per log10 Treg, p=0.00028), with a similar trend for Th17 cells (p=0.09). Selectively increasing endocervical Tregs may represent a pathway to reduce genital tract inflammation in women.
Highlights
Genital inflammation defined by elevated levels of proinflammatory cytokines in mucosal secretions has been associated with ~3-fold increased HIV acquisition and diminished topical pre-exposure prophylaxis (PrEP) efficacy in women (1, 2)
We found that cervicovaginal Tregs were associated with decreased genital inflammation and reduced frequencies of HIV target cell abundance, suggesting that increasing this cell population may represent a mechanism for better control of genital inflammation
Prior pre-exposure prophylaxis (PrEP) access was relatively common at 55% (35/ 64), and approximately one-quarter (17/64, 27%) had reported
Summary
Genital inflammation defined by elevated levels of proinflammatory cytokines in mucosal secretions has been associated with ~3-fold increased HIV acquisition and diminished topical PrEP efficacy in women (1, 2). Additional work by our group has demonstrated that elevated cervicovaginal cytokines coincide with higher numbers of HIV target cells and a decrease in proteins associated with mucosal barrier function, providing a potential mechanism linking genital inflammation with HIV acquisition (3). In this model, inflammatory cytokines recruit immune cells, which in turn secrete proteins that contribute toward mucosal tissue damage and further cytokine release, perpetuating a cycle of impaired barrier function and more target cell recruitment for HIV to establish a localized infection (4). The balance and distribution of Tregs could have important implications for inhibition of specific inflammatory processes in tissues
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