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Problem: Chlamydia trachomatis infection is the most common sexually transmitted bacterial infection worldwide and known to increase the risk for HIV acquisition. Few studies have investigated how infection of epithelial cells compromises barrier integrity and antimicrobial response., Method of Study: ECC-1 cells, a human uterine epithelial cell line, were treated with live and heat-killed C. trachomatis. Epithelial barrier integrity measured as transepithelial resistance (TER), chemokines antimicrobial levels, and antimicrobial mRNA expression was measured by ELISA and Real-time RT-PCR., Results: Epithelial barrier integrity was compromised when cells were infected with live, but not with heat-killed, C. trachomatis. IL-8 secretion by ECC-1 cells increased in response to live and heat-killed C. trachomatis, while MCP-1, HBD2 and trappin2/elafin secretion decreased with live C. trachomatis., Conclusion: Live C. trachomatis suppresses ECC-1 innate immune responses by compromising the barrier integrity, inhibiting secretion of MCP-1, HBD2, and trappin-2/elafin. Differential responses between live and heat-killed Chlamydia indicate which immune responses are dependent on ECC-1 infection rather than the extracellular presence of Chlamydia., (© 2017 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.)

Problem: New HIV infections in women are predominantly spread through sexual intercourse. Recent non-human primate studies demonstrated that simian immunodeficiency virus (SIV) deposited in the vagina infected immune cells in the ovary. Whether immune cells in the human ovary are susceptible to HIV infection is unknown., Method of Study: Immune cells were isolated from ovaries and characterized by flow cytometry. Cells were exposed to HIV for 2 hours. HIV infection was measured by flow cytometry and p24 secretion following 6 days in culture., Results: CD4 + T cells and CD14 + cells are present in the ovary and susceptible to infection by HIV-BaL. Among the CD45 + cells present, 30% were CD3 + T cells (with similar proportions of CD4 + or CD8 + T cells), and 7%-10% were CD14 + cells. Both CD4 + T cells and CD14 + cells were productively infected and supported replication., Conclusion: Immune cells in the ovary are potential targets for HIV infection., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Problem: The programmed death 1 (PD-1)/PD-L1 pathway regulates peripheral tolerance, immune responses, and is up-regulated in chronic viral infections, including HIV infection. However, expression of PD-1/PD-L1 on immune cells from the human female reproductive tract (FRT) and possible regulation by menopause and sex hormones are poorly understood., Method of Study: PD-1/PD-L1 expression was analyzed on CD4(+) and CD8(+) T cells, CD163(+) macrophages, and CD11c(+) dendritic cells (DC) from endometrium (EM), endocervix (CX) and ectocervix (ECX). Expression after hormone treatment in culture was also evaluated., Results: PD-1 and PD-L1 were constitutively expressed on CD4(+) and CD8(+) T cells from the FRT. PD-L1(+) CD4(+) T cells were increased in CX compared to EM and ECX, while no differences were found for PD-1 or between CD8(+) T cells from different sites. Macrophages and DCs constitutively expressed PD-L1, but not PD-1, with no differences observed between FRT sites. Pre-menopausal FRT tissues showed increased PD-L1 expression on CD8(+) T cells, but decreased expression on DCs when compared to post-menopausal women. In vitro estradiol treatment up-regulated PD-L1 expression specifically on CD8(+) T cells from CX, but had no effect on PD-1/PD-L1 expression on the other cell types., Conclusion: Our results suggest that PD-L1 may be involved in the differential regulation of FRT immune responses between pre-menopausal and post-menopausal women., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The immune system in the female reproductive tract (FRT) does not mount an attack against human immunodeficiency virus (HIV) or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the FRT. Working together, these antimicrobials along with mucosal antibodies attack viral, bacterial, and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus, has evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol (E2 ) and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells, fibroblasts and immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate and adaptive immune systems are under hormonal control, that protection varies with the stage of the menstrual cycle and as such, is dampened during the secretory stage of the cycle to optimize conditions for fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Studies on HIV acquisition and transmission in women exposed to sexual trauma throughout their life cycle are lacking, but some findings suggest that rates of HIV acquisition through coercive sex are significantly higher than that seen in consensual sex. Sexual trauma can also occur as a result of female genital mutilation, which makes sex extremely painful and can cause increased abrasions, lacerations, and inflammation, which enhances the risk of HIV acquisition. This review presents an overview of the immune system in the human female reproductive tract (FRT) from adolescence, through puberty to pregnancy and menopause. What is clear is that the foundation of information on immune protection in the FRT throughout the life cycle of women is extremely limited and at some stages such as adolescence and menopause are grossly lacking. Against this backdrop, forced or coercive sexual intercourse as well as genital mutilation further complicates our understanding of the biological risk factors that can result in transmission of HIV and other sexually transmitted infections., (© 2012 John Wiley & Sons A/S.)