The impact of aging on innate and adaptive immunity in the human female genital tract

Abstract

Mucosal tissues in the human female reproductive tract (FRT) are primary sites for both gynecological cancers and infections by a spectrum of sexually transmitted pathogens, including human immunodeficiency virus (HIV), that compromise women's health. While the regulation of innate and adaptive immune protection in the FRT by hormonal cyclic changes across the menstrual cycle and pregnancy are being intensely studied, little to nothing is known about the alterations in mucosal immune protection that occur throughout the FRT as women age following menopause. The immune system in the FRT has two key functions: defense against pathogens and reproduction. After menopause, natural reproductive function ends, and therefore, two overlapping processes contribute to alterations in immune protection in aging women: menopause and immunosenescence. The goal of this review is to summarize the multiple immune changes that occur in the FRT with aging, including the impact on the function of epithelial cells, immune cells, and stromal fibroblasts. These studies indicate that major aspects of innate and adaptive immunity in the FRT are compromised in a site-specific manner in the FRT as women age. Further, at some FRT sites, immunological compensation occurs. Overall, alterations in mucosal immune protection contribute to the increased risk of sexually transmitted infections (STI), urogenital infections, and gynecological cancers. Further studies are essential to provide a foundation for the development of novel therapeutic interventions to restore immune protection and reverse conditions that threaten women's lives as they age.

Keywords: Dendritic cells; TGFβ; epithelial cells; female reproductive tract; fibroblasts; menopause; resident memory T cells; sex hormones; sexually transmitted infections.

FIGURE 1

Diagram of the human female reproductive tract (FRT) showing the major tissue compartments. The upper FRT includes the fallopian tubes, endometrium, and endocervix, which are lined with columnar epithelial cells. The lower FRT consists of the ectocervix and vagina which is lined with squamous epithelial cells. The reproductive and immunological functions of each site are separate and distinct. Each site functions to optimize conditions for successful fertilization and implantation while protecting against sexually transmitted pathogens. Adapted from (Wira et al., 2015)

FIGURE 2

Regulation of epithelial cell and fibroblast function by menopausal status. This diagram shows key epithelial and stromal fibroblast functions and how they are modified after menopause. Triangles indicate a decline in cell function with menopause. A rectangle indicates no change following menopause. Effects are shown for the endometrium on the upper part and for the cervix (endocervix and ectocervix) on the lower part of the figure

FIGURE 3

Regulation of CD8+ T‐cell function in the FRT by menopausal status. This diagram indicates key T‐cell functions that are modified after menopause. As indicated by the shape of each triangle, some functions decline while others increase after menopause. Rectangles indicate no change. Effects are shown for the endometrium on the upper part and for the cervix (endocervix and ectocervix) on the lower part of the figure

FIGURE 4

Regulation of DC distribution function in the FRT by menopausal status. This diagram shows key DC functions that are modified after menopause. Specific functions decline or increase after menopause as indicated. Rectangles indicate no change; those containing a question mark (?) indicate that changes are unknown. Effects are shown for the endometrium on the upper part and for the cervix (endocervix and ectocervix) and vagina on the lower part of the figure