The role of sex hormones and the tissue environment in immune protection against HIV in the female reproductive tract

Abstract

Despite extensive studies of the mucosal immune system in the female reproductive tract (FRT) and its regulation by sex hormones, relatively little attention has been paid to the tissue environment in the FRT that regulates immune cell function. Consisting of secretions from epithelial cells (EC), stromal fibroblasts, and immune cells in tissues from the upper (Fallopian tubes, uterus, and endocervix) and lower (ectocervix and vagina) tracts, each tissue compartment is unique and precisely regulates immune cells to optimize conditions for successful pregnancy and protection against sexually transmitted diseases including HIV. Our goal in this review is to focus on the mucosal (tissue) environment in the upper and lower FRT. Specifically, this review will identify the contributions of EC and fibroblasts to the tissue environment and examine the impact of this environment on HIV-target cells. Much remains to be learned about the complex interactions with the tissue environment at different sites in the FRT and the ways in which they are regulated by sex hormones and chemical contraceptives. Awareness of the involvement of the tissue environment in determining immune cell function and HIV acquisition is crucial for understanding the mechanisms that lead to HIV prevention, acquisition, and the development of new therapeutic modalities of immune protection.

Keywords: Epithelial cells; estradiol; female reproductive tract; fibroblasts; innate and adaptive immune systems; sex hormones.

Figure 1

Representation of tissue environment immune protection against HIV in the female reproductive tract. Sex hormones regulate cellular interaction and communication between epithelial cells, fibroblasts and HIV-target cells to provide defense against HIV infection.

Figure 2

Basolateral conditioned media (CM) from primary polarized epithelial cells inhibit trans infection by immature dendritic cells (iDC). The effect of primary uterine epithelial cell CM on trans infection by DC of HIV-1 infectious molecular clones encoding envelope ectodomains (env-IMC) of reference HIV-1 (BaL or YU-2) is shown. Media or CM from the basolateral compartments of primary uterine epithelial cells grown in cell inserts were incubated with immature DC differentiated from human monocyte derived-dendritic cells. Immature DC were pulsed with HIV-1 derived from infectious mononuclear clones expressing env genes for BaL or YU-2 in an isogenic reporter background. HIV-1 trans infection assay was performed using TZM-bl reporter cells as targets. Virus-pulsed DC were co-cultured with the TZM-bl reporter cell line and virus infection was assayed by measuring β-galactosidase expression with a Luminometer. The data are presented as % transmission +/− SEM (Calculated from 5 separate experiments) of HIV-1 by CM DC relative to Control DC. * p<0.05, ** p<0.001. Similar results were obtained with 4 transmitted/founder HIV-1. From .

Figure 3

Effect of 48hr fibroblast conditioned media (CM) derived from 4 patients on the infection of HIV BaL. TZM-bl cells were incubated with media control, Bal, or Bal and CM from quadruplicate fibroblast cultures of 4 patients. Relative Light Units (RLU) of β-galactosidase expression were determined with a Luminometer. Conditioned Media from three out of four fibroblast cell cultures significantly decreased infection. **, p<0.01, ***, p<0.001.

Figure 4

Basolateral conditioned media from uterine and endocervical EC up-regulates CX3CR1 expression in CD4⁺T cells. CD4⁺T cells were purified from peripheral blood, incubated with basolateral EC conditioned media (CM) from the endometrium, endocervix and ectocervix for 48hr and analyzed for CX3CR1 expression by flow cytometry. CM from endometrium and endocervix, but not ectocervix up-regulated the expression of CX3CR1 compared to control cells incubated with media alone.

Figure 5

Basolateral CM from purified polarized uterine epithelial cell and fibroblast CM down-regulate CCR5 but not CXCR4 mRNA expression in CD4⁺T cells. Purified blood T cells were incubated with CM from primary cultures of uterine epithelial cells and fibroblasts for 24hr. mRNA was isolated and expression of CCR5 and CXCR4 determined by RT-PCR. These findings provide direct evidence that basolateral secretions from FRT epithelial cells and fibroblasts alter susceptibility to HIV infection. **, Significantly p<0.01 lower than control cells.