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The role of sex hormones in immune protection of the female reproductive tract

Key Points

  • Interactions between the innate and adaptive immune systems and the endocrine system in the female reproductive tract (FRT) are essential for successful reproduction and for maintaining immune protection against sexually transmitted infections.

  • Epithelial cells, fibroblasts and immune cells throughout the FRT contribute to immune protection and create a mucosal environment that supports reproduction.

  • Immune cell number, tissue distribution, phenotype and function throughout the menstrual cycle are site-specific in the lower and upper FRT and are differentially regulated by sex hormones. Hormonal regulation of immune cells in the endometrium is required to prevent sperm rejection and to prepare the endometrial tissue for implantation.

  • Epithelial cells, fibroblasts and immune cells at each site are hormonally regulated and influence one another through the secretion of growth factors, cytokines, chemokines and antimicrobial factors.

  • Immune protection that is regulated by oestradiol and progesterone is characterized by phenotypic changes to cells, including alterations to the secretion of cytokines, chemokines and antimicrobial factors, receptor expression, barrier function, cellular responses to pathogens, and the distribution and function of immune cells.

  • Immune regulation to achieve optimal conditions for fertilization, implantation and pregnancy creates a 'window of vulnerability' during the secretory phase of the menstrual cycle, such that HIV and possibly other sexually transmitted pathogens are able to breach and infect the FRT.

Abstract

Within the human female reproductive tract (FRT), the challenge of protection against sexually transmitted infections (STIs) is coupled with the need to enable successful reproduction. Oestradiol and progesterone, which are secreted during the menstrual cycle, affect epithelial cells, fibroblasts and immune cells in the FRT to modify their functions and hence the individual's susceptibility to STIs in ways that are unique to specific sites in the FRT. The innate and adaptive immune systems are under hormonal control, and immune protection in the FRT varies with the phase of the menstrual cycle. Immune protection is dampened during the secretory phase of the cycle to optimize conditions for fertilization and pregnancy, which creates a 'window of vulnerability' during which potential pathogens can enter and infect the FRT.

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Figure 1: Anatomy and histology of the FRT.
Figure 2: The menstrual cycle.
Figure 3: Fluctuations in immune cell populations in the FRT during the menstrual cycle.
Figure 4: Oestradiol-mediated control of interactions between epithelial cells, fibroblasts and immune cells in the FRT.
Figure 5: Influence of sex hormones on mucosal immunity in the lower and upper FRT during the window of vulnerability.

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Acknowledgements

The authors express their appreciation to J. Fahey for help in editing this manuscript. This work was supported by US National Institutes of Health (NIH) grants AI102838, AI071761 and AI117739.

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Glossary

Implantation

The binding to and invasion of the uterine endometrium by the blastocyst, which occurs 5–12 days after fertilization.

Proliferative phase

Days 5–14 of the classical menstrual cycle. Defined as the period between the end of menstrual bleeding and ovulation. Characterized by rising serum levels of oestradiol and very low levels of progesterone.

Secretory phase

Days 14–28 of the classical menstrual cycle. Defined as the period between ovulation and the initiation of menstrual bleeding. Characterized by high levels of both oestradiol and progesterone.

Corpus luteum

The tissue formed after ovulation by thecal and granulosa cells from the remains of the collapsed ovarian follicle; it is responsible for progesterone and oestradiol secretion during the secretory phase of the menstrual cycle. In the absence of fertilization, the corpus luteum degrades, thus decreasing hormone synthesis and signalling the initiation of menstruation.

Pattern-recognition receptors

(PRRs). Multiple families of conserved receptors, such as Toll-like receptors (TLRs), that are present on the cell surface or within intracellular compartments. PRRs recognize conserved structures that are present on pathogens or that are produced as part of their life cycle.

Pathogen-associated molecular patterns

(PAMPs). Conserved structures that are an integral part of pathogens but not mammalian cells and that are recognized by pattern- recognition receptors. Examples include viral and bacterial components such as double- and single-stranded RNA, bacterial lipopolysaccharide and hypomethylated DNA.

Cervico-vaginal lavage fluid

(CVL fluid). The fluid recovered after gently washing the vaginal walls and external cervix; it contains the cellular secretions present in the lower female reproductive tract.

Tight junction proteins

A group of proteins, including claudins and occludin, that form complexes to link adjacent epithelial cells, creating a polarized epithelium that provides a barrier and regulates the movement of molecules.

Decidualization

The changes to the endometrium that occur as it transitions to a pregnant state under the influence of progesterone. Characterized by vascular, stromal and epithelial changes that create a permissive uterine environment for implantation.

TZM-bl cells

Modified HeLa cells that express high levels of the HIV receptor CD4, the co-receptors CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4), and a Tat-induced β-galactosidase cassette.

Lamina basalis

The lower layer of the uterine endometrium that is not shed at menses and from which the functionalis layer is reconstituted during the proliferative phase of the menstrual cycle.

Functionalis layer

The upper layer of the uterine endometrium that is shed at menses.

Innate lymphoid cell

(ILC). An innate immune cell with classical lymphoid morphology that lacks cell lineage markers and antigen specificity. ILCs are heterogeneous and include cytotoxic natural killer cells and cytokine-producing non-cytotoxic helper ILC populations.

Alternatively activated macrophages

Macrophages that have been activated by the T helper 2 cell-type cytokines interleukin-4 (IL-4) and IL-13, as opposed to the classical interferon-γ (IFNγ) activation pathway. Alternative activation confers a phenotype that is instrumental in immune regulation and tissue repair.

Viral eclipse phase

The interval of time after viral infection during which the virus cannot be detected.

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Wira, C., Rodriguez-Garcia, M. & Patel, M. The role of sex hormones in immune protection of the female reproductive tract. Nat Rev Immunol 15, 217–230 (2015). https://doi.org/10.1038/nri3819

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