Effect of hormonal contraception on the function of plasmacytoid dendritic cells and distribution of immune cell populations in the female reproductive tract

Abstract

Objective: Epidemiological evidence suggests an association between the use of hormonal contraception and an increased risk of acquiring sexually transmitted diseases including HIV-1. We sought to elucidate the biological mechanisms underlying the effect of hormonal contraception on the immune system.

Design: Cross-sectional study.

Methods: To delineate the biological mechanisms underlying the effect of hormonal contraceptives on the immune system, we analyzed the functional capacity of circulating plasmacytoid dendritic cells (pDCs), the distribution of vaginal immune cell populations, and the systemic and genital levels of immune mediators in women using depot medroxyprogesterone acetate (DMPA), NuvaRing, or combined oral contraceptives (COC).

Results: The use of DMPA or NuvaRing was associated with reduced capacity of circulating pDCs to produce interferon (IFN)-α and tumor necrosis (TNF-α) in response to TLR-9 stimulation. Systemic levels of IFN-α and cervicovaginal fluid levels of IFN-α, CXCL10, monocyte chemotactic protein-1, and granulocyte-colony stimulating factor were significantly lower in DMPA users compared to control volunteers not using hormonal contraception. The density of CD207 Langerhans cells in the vaginal epithelium was reduced in NuvaRing and combined oral contraceptive users but not in DMPA users.

Conclusions: The presented evidence suggests that the use of some types of hormonal contraception is associated with reduced functional capacity of circulating pDCs and altered immune environment in the female reproductive tract.

Figure 1. Plasmacytoid dendritic cells (pDCs) from NuvaRing and DMPA users display reduced ability to produce IFNα and TNFα in response to stimulation via TLR-9

PBMCs were isolated from 20 control volunteers not using any form of hormonal contraception, 17 DMPA users, 14 NuvaRing users, and 13 COC users, and stimulated with 2 µM TLR-9 ligand CpG ODN2216 or 5µg/mL TLR-7/8 ligand R848. A) Gating strategy for the analysis of intracellular production of IFNα and TNFα in pDCs identified as CD123⁺ CD303⁺ population. B-E) Intracellular cytokine staining for IFNα (B, D) or TNFα (C, E) in pDCs was performed in PBMCs stimulated with CpG (B,C) or R848 (D,E). Values are corrected for background staining of unstimulated cells. Bars indicate median values; statistical significance was determined using the Mann-Whitney U test.

Figure 2. DMPA use is associated with lower levels of plasma IFNα and IL-8

Plasma from 21 control volunteers, 19 DMPA, 14 NuvaRing, and 14 COC users were analyzed for the concentrations of IFNα (A) and IL-8 (B). Bars indicate median values; significance was determined using the Mann-Whitney U test.

Figure 3. DMPA use is associated with lower levels of IFNα, CXCL10, MCP-1, G-CSF, TIMP-1 and TIMP-2 in the cervicovaginal fluid

Cervicovaginal lavages from 21 controls, 20 DMPA, 14 NuvaRing, and 14 COC users were analyzed for chemokine, cytokine, MMP-7 and -9, and TIMP-1 and -2 concentrations. Bars indicate median values; significance was established using Mann-Whitney U test.

Figure 4. Density and shortest apical distance of vaginal intraepithelial Langerhans and CD3⁺ T cells are altered in users of hormonal contraception

Vaginal biopsies obtained from DMPA, NuvaRing, and COC users and control volunteers were sectioned at 30 µm and stained for CD207⁺ Langerhans cells (A, C) and CD3⁺ T cells (B,D). Intraepithelial density (A,B) and shortest distance to the apical epithelial surface (C,D) of Langerin⁺ (A, C) and CD3⁺ (B, D) cells was analyzed. Bars indicate median value for each group; significance was determined using Mann-Whitney U test.