Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection

Abstract

The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections.

Figure 1

Anatomical and immunological components of the female reproductive tract. The female reproductive tract consists of an upper (fallopian tubes, uterus and endocervix) and a lower (extocervix and vagina) tract. The vaginal epithelium has many innate immune-mediated protection mechanisms, such as tight junctions, AMPs and mucus, to neutralize, trap, and prevent the entry of potential pathogens. The vaginal lumen is colonized by commensal bacteria, mainly Lactobacilli spp., which help maintain a low pH environment and produce reactive oxygen species. Furthermore, innate immune cells, such as γδ T cells, DCs, and macrophages, are present beneath and between vaginal epithelial cells layer to survey the local environment for danger. The abrupt transition from keratinized squamous epithelial cells of the ectocervix to single columnar epithelial cells of the endocervix represents the transformation zone; this site has an abundance of HIV target cells (DCs and CD4⁺ T cells) and has been proposed to be one of the major sites of infection. Although traditional mucosal lymphoid structures are not found in the female reproductive tract, lymphoid aggregates in the endometrial tissue that are composed of B cells in the inner core and surrounded by CD8⁺CD4⁻ T cells and an outer layer of macrophages have been described. Scattered CD56⁺ NK cells and CD4⁺ T cells can be found between lymphoid aggregates. The immune cells and functions of the female reproductive tract are regulated by sex hormones that orchestrate cyclical changes with the menstrual cycle. AMP, anti-microbial peptide; DC, dendritic cell; NK, natural killer.

Figure 2

Anatomical and immunological components of the male reproductive tract. The MRT is composed of two main parts—the penile urethra and the testes. The opening of the penile urethra transitions from keratinized stratified squamous epithelium to non-keratinized stratified squamous epithelium in the fossa navicularis. As the non-keratinized stratified squamous epithelium enters the shaft of the penis, it transitions into the pseudostratified glandular columnar epithelium, which lines the length of the penile urethra. Within the epithelium of the penile urethra are deep invaginations, known as Littre glands, which provide lubricating pre-ejaculate for sexual intercourse and contribute to innate immunity by producing AMPs. Urethral pseudostratified columnar epithelium is an active immune microenvironment that contains CD8⁺ and CD4⁺ T cells, NK cells, dendritic cells and resident macrophages, which have been found to be key targets for HIV infection in the penile urethra. IgG, IgA and IgM immunoglobulins are also secreted from the urethra epithelium, along with Type 1 IFN, mucins and AMPs. The testes are the main site of spermatogenesis, which begins in the rete testes and seminiferous tubules; mature spermatozoa enter the epidiymis. Seminiferous tubules, located within the lobules of the testes, are made up of Sertoli cells that are surrounded by a basement membrane. Sertoli cells aid in spermatogenesis but also express TLRs. Within the interstitial space of the seminiferous tubules are Leydig cells, which produce testosterone and estradiol, and PMCs, which regulate testes development and spermatogenesis by secreting TGF-β2, MCP-1 and LIF. Resident ED2⁺ macrophages, which have an attenuated inflammatory function, are found within the interstitial spaces of the MRT along with regulatory T cells—both cell types contribute to the immunoregulatory microenvironment of the testes. AMP, anti-microbial peptide; IFN, interferon; Ig, immunoglobulin; LIF, leukemia inhibitory factor; MCP, monocyte chemoattractant protein; MRT, male reproductive tract; NK, natural killer; PMC, peritubular myoid cell; TGF, transforming growth factor; TLR, Toll-like receptor.