Endocervical Regulatory T Cells Are Associated With Decreased Genital Inflammation and Lower HIV Target Cell Abundance

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.

The female reproductive tract microbiotas, inflammation, and gynecological conditions

“…There is an inverse association between T-regs and pro-inflammatory cytokines in the endocervix; a higher frequency of endocervical Treg is associated with lower pro-inflammatory cytokines, such as IL-1β, IL-8, G-CSF, MIP-1β, Eotaxin, and IL-1RA ( 107 ). A higher endocervical T-regs concentration is also associated with lower CD4 + T cells which are required for human immunodeficiency virus (HIV) to establish itself in the mucosa, further suggesting an anti-inflammatory role for Tregs in FRT ( 107 ). Taken together, the are many knowledge gaps regarding the role of Tregs in FRT which need to be addressed in future studies.…”

Exploring Immunome and Microbiome Interplay in Reproductive Health: Current Knowledge, Challenges, and Novel Diagnostic Tools

“…[111][112][113] Increased endocervical Tregs have been linked to reduced proinflammatory cytokine and CD4þ T cell counts. 114 Antigen-presenting cells (APC), such as DCs, can contribute to Treg selection through the TGF-β and retinoic acid (RA) signaling pathways. 115,116 Furthermore, microbiota can activate TLR4 at lower FRT to further support immune tolerance.…”

Role of the human vaginal microbiota in the regulation of inflammation and sexually transmitted infection acquisition: Contribution of the non-human primate model to a better understanding?

“…Moreover, vaginal inoculation of P. bivia in germ free mice promoted the recruitment in the FRT of CCR5 + CD4 + T cells compared to mice inoculated with L. crispatus ( 47 ). A. Semaganda et al suggested that Treg might be important in the regulation of inflammation induced by BV associated bacteria but do not affect directly the presence of BV associated bacteria ( 48 ). Cervical cytobrushes of HIV exposed seronegative women (HESN) exhibited an increased frequency of NK cells, CXCR5 + CD8 + T cells, follicular T cells compared to HIV unexposed healthy women.…”