The mucosal immune system in the female reproductive tract (FRT) has evolved to meet the unique requirements of dealing with sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and the immunologically distinct fetus. Analysis of the FRT indicates that the key cells of the innate and adaptive immune systems are present and functionally responsive to antigens. Acting through Toll-like receptors in the Fallopian tubes, uterus, cervix, and in the vagina, epithelial cells, macrophages, natural killer cells, and neutrophils confer protection through the production of chemokines and cytokines, which recruit and activate immune cells, as well as bactericidal and virucidal agents, which confer protection at times when adaptive immunity is downregulated by sex hormones to meet the constraints of procreation. The overall goal of this paper is to define the innate immune system in the FRT and, where possible, to define the regulatory influences that occur during the menstrual cycle that contribute to protection from and susceptibility to potential pathogens. By understanding the nature of this protection and the ways in which innate and adaptive immunity interact, these studies provide the opportunity to contribute to the foundation of information essential for ensuring reproductive health.

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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SUMMARYThe objective of this study was to examine the expression of toll-like receptors (TLRs) by the uterine epithelial cell line ECC-1 and to determine if stimulation of the expressed TLRs induces changes in cytokine and ⁄or chemokine secretion. The expression of TLR1 to TLR9 by ECC-1 cells was demonstrated by reverse transcription polymerase chain reaction, with only TLR10 not being expressed. Stimulation of ECC-1 cells using agonists to TLR2, TLR4 and TLR5 induced the expression of the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1), as well as the pro-inflammatory cytokine IL-6, and occurred in a dose-dependent manner. In response to zymosan and flagellin, pathogen-associated molecular patterns (PAMP) that are recognized by TLR2 and TLR5 respectively, ECC-1 cells secreted significantly more IL-8, MCP-1 and IL-6 than in response to other TLR agonists. In contrast, agonists to TLR3, TLR7, and TLR9 had no effect on the secretion of the 13 cytokines or chemokines analysed. These results indicate that uterine epithelial cells are important sentinels of the innate immune system. Further it indicates that all but one of the known TLRs are expressed by ECC-1 cells and that stimulation through specific TLRs mediates changes in the expression of key chemokines and pro-inflammatory cytokines that aid in the defence of the uterus against potential pathogens.

This review examines the multiple levels of pre-existing immunity in the upper and lower female reproductive tract. In addition, we highlight the need for further research of innate and adaptive immune protection of mucosal surfaces in the female reproductive tract. Innate mechanisms include the mucus lining, a tight epithelial barrier and the secretion of antimicrobial peptides and cytokines by epithelial and innate immune cells. Stimulation of the innate immune system also serves to bridge the adaptive arm resulting in the generation of pathogen-specific humoral and cell-mediated immunity. Less understood are the multiple components that act in a coordinated way to provide a network of ongoing protection. Innate and adaptive immunity in the human female reproductive tract are influenced by the stage of menstrual cycle and are directly regulated by the sex steroid hormones, progesterone and estradiol. Furthermore, the effect of hormones on immunity is mediated both directly on immune and epithelial cells and indirectly by stimulating growth factor secretion from stromal cells. The goal of this review is to focus on the diverse aspects of the innate and adaptive immune systems that contribute to a unique network of protection throughout the female reproductive tract.