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.

public health challenge that must be addressed. The incidence of STIs has increased by 38% since 2010 in the 50-70 year age group (CDC, 2016a(CDC, , 2016b. UTIs are often caused by Escherichia coli (Hu et al., 2004), which colonize the FRT in older women prior to spreading to the urinary tract Hummelen et al., 2011).
Sexual activity is a risk factor for STIs and some UTIs, the prevalence of which is not widely recognized in older adults (CDC, 2016a;Hu et al., 2004;Taylor et al., 2017).
In addition to genitourinary infections, aged women have a high burden of comorbidities associated with endometrial, ovarian, and cervical cancers (CDC, 2019). Uterine cancer is the most common gynecological cancer worldwide and the sixth most common cause of cancer death which occurs primarily in postmenopausal women, with an average age of diagnosis of 60 years (Henley et al., 2020;Lu & Broaddus, 2020). Accompanying this is an increase in human papillomavirus (HPV) (types 16 and 18), the underlying cause of cervical cancer and precancerous lesions (Chan et al., 2019;Gonzalez et al., 2010;Gravitt et al., 2013;Rositch et al., 2012). Despite the burden of STIs and gynecological cancer in older women, they are not recognized as a clinical priority. Aged women are also generally excluded from STI prevention trials (Herrera et al., 2010), vaccination recommendations, and prevention advice (Granville & Pregler, 2018). Thus, there is a critical need to understand how, as women age, immune protection against STIs and cancer changes in the FRT-the primary mucosal surface where pathology initiates.

| UNI QUENE SS OF THE AG ING PRO CE SS IN THE FRT: MENOPAUS E AND AG ING IN WOMEN
The aging process in women is accompanied by the transition into menopause. Menopause marks the end of natural reproductive potential with the permanent secession of menstrual cycles, caused by the decline in ovarian sex hormone production (estradiol and progesterone) (Maruoka et al., 2014). Since the average age at menopause is 50 years (Palacios et al., 2010), and the average life expectancy of women in the USA is 78 years, women live for 30-40 years in a postmenopausal environment with low concentrations of sex hormones.
How this hormone-deprived environment affects immune function overtime is of great importance in understanding the mechanisms involved in immune protection in older women. Importantly, longterm survival after menopause cannot be fully reproduced in animal models (Walker & Herndon, 2008), highlighting the importance of studying aging effects with human samples.
Not widely appreciated is that the immune system in the FRT is critical for reproductive success. Sex hormones tightly regulate immune function in the premenopausal FRT to ensure the balance between optimal conditions for pregnancy and protection against pathogens (Wira et al., 2015). To achieve this necessary balance, the FRT has evolved with distinct anatomical compartments consisting of the fallopian tubes, uterus (endometrium), endo-and ectocervix, and vagina ( Figure 1). As reviewed elsewhere (Wira et al., 2015), each compartment contains adaptive and innate immune cells, but each site is separate and distinct regarding reproductive function and immune protection prior to menopause. Following menopause, immune cell populations and responses are dramatically altered. As women age, two interrelated processes overlap and contribute to changes in immune protection in the FRT: menopause and immunosenescence. While much is known about the effects of sex hormones on immune function in the FRT during the menstrual cycle, relatively little is known about the immunosenescent changes that occur after menopause and in the years that follow.
In this review, we consider immunosenescence throughout the FRT. We focus on changes in mucosal immune function following menopause and how they relate to potential changes on susceptibility to infections and the risk of gynecological cancers. Beyond the scope of this review are age-related changes in the ovary, vulva, and other anatomically proximal organs, such as bladder and rectum, which contribute to morbidity in older women. Overall, following menopause, a growing body of evidence indicates that aging significantly alters adaptive and innate immunity, in ways that are distinct and site-specific throughout the FRT.

| CHANG E S IN EPITHELIAL CELL S AND BARRIER PROTEC TI ON INDUCED BY AG ING
Epithelial cells line the surface of the FRT and are the first line of defense against incoming pathogens. They contribute to immune protection by (a) providing a physical barrier that separates the F I G U R E 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) internal and external environments; (b) providing a chemical barrier composed of mucus, antimicrobials, cytokines, and chemokines that directly interact with pathogens and modulate the local immune system; and (c) mounting rapid innate immune responses to pathogens via pattern recognition receptors (PRRs). Little is known about how FRT epithelial functions change with age in postmenopausal women, since most studies focus on younger reproductive-aged women.

| Barrier protection
Epithelial cells form a physical barrier that protects underlying FRT tissues and its resident immune cells against potential pathogens and injuries. Epithelial cell phenotype varies with anatomical location in the FRT. The stratified squamous epithelium of the lower FRT (ectocervix and vagina) is 25-50 layers thick with superficial, parabasal, and basal layers (Patton et al., 2000). In contrast, the upper FRT (endocervix, endometrium, and fallopian tubes) is covered by a single layer of columnar epithelial cells. Whether increased barrier thickness correlates with increased protection against pathogens in the lower FRT is unclear. However, cervical ectopy, where columnar epithelium of the endocervix extrudes onto the surface of the ectocervix, is associated with increased transmission risk of HIV (Moss et al., 1991), human papillomavirus (HPV) (Rocha-Zavaleta et al., 2004), Chlamydia trachomatis (Lee et al., 2006), and cytomegalovirus (CMV) (Critchlow et al., 1995).
Postmenopausal women have a thinner vaginal epithelium (21.4 vs 10.7 cell layers) compared to premenopausal women (Thurman et al., 2017), suggesting decreased barrier protection in the lower FRT. There is also a loss of hydration which leads to increased vaginal dryness, irritation, and inflammation. Loss of natural lubrication can lead to epithelial damage during sexual intercourse, potentially increasing pathogen access to the underlying tissue. Furthermore, epithelial wound healing is compromised following menopause in animal models Shveiky et al., 2020), at other mucosal sites (Engeland et al., 2009;Horng et al., 2017) and in cell culture (Patel, M. Unpublished).
Tight junction and adherens junction protein complexes link adjacent epithelial cells and serve as a selectively permeable barrier that allows movement of proteins and solute across the epithelium (Anderson & Van Itallie, 2009;Blaskewicz et al., 2011). Tight junctions are primarily composed of ZO-1, occludin, and multiple claudin proteins, while adherens junctions are composed of N-, P-and O-cadherin. Tight junctions are precisely regulated throughout the menstrual cycle by sex hormones in premenopausal women (Fahey et al., 2006;Gorodeski, 2001aGorodeski, , 2007Gorodeski et al., 2005;Iwanaga et al., 1985;Murphy et al., 1992;Zeng et al., 2004). While the effect of aging on tight and adherens junction expression in the FRT is relatively unknown, vaginal epithelial E-cadherin levels are lower in postmenopausal women than premenopausal women (Thurman et al., 2017). Furthermore, levels of paracellular permeability and transcellular resistance are lower in ectocervical cultures from postmenopausal women compared to premenopausal women (Gorodeski, 2001b). Since pathogens such as HIV can also decrease tight junction integrity between endometrial epithelial cells (Mukura et al., 2017;Nazli et al., 2010), aging may exacerbate the movement of pathogens into the underlying tissue. Thus, aging potentially leads to an overall decrease in FRT epithelial barrier protection ( Figure 2).

| Pattern Recognition Receptors (PRRs)
PRRs are essential for the recognition and response to pathogens.
PRRs include Toll-like receptors (TLR) and retinoic acid inducible gene (RIG)-like receptors (RLR), which recognize conserved moieties known as pathogen-associated molecular patterns (PAMPs) characteristic of broad classes of pathogens. PRR expression varies within the FRT by anatomical location and cell type (Pioli et al., 2004;Zarember & Godowski, 2002). Human endometrial epithelial cells express TLRs1-9, with TLR1, 2, 3, and 5 being expressed at the highest levels . Vaginal epithelial cells express TLR1, 3, 5, and 6, but not TLR4 (Fichorova et al., 2002). At the tissue level, TLR4, RIG-I, MDA5, NOD1, and NOD2 expressions are highest in the upper FRT and decline in the lower FRT Pioli et al., 2004). TLR2 expression is highest in the fallopian tubes and cervix but lowest in the endometrium and ectocervix. In contrast, TLR7, 8, and 9 are consistently expressed from the fallopian tubes to ectocervix (Hart et al., 2009). TLR expression varies with menstrual cycle stage and is lower in endometrial tissues at the proliferative phase compared to the secretory phase. Endometrial epithelial immune responses are partially regulated by sex hormones. Estradiol decreases secretion of IL-6, IL-8, and MIF by endometrial epithelial cells in response to TLR3 or TLR4 stimulation (Fahey et al., 2008;Lesmeister et al., 2005). How the decline in ovarian sex hormones affects epithelial innate immune responses to PRR ligands is unclear. In preliminary studies with endometrial epithelial cells, we discovered a trend toward decreased TLR3 expression in older women (>75 years) compared to younger women (50-59 years) ( Figure 2). Since exposure to the TLR3 agonist poly(I:C) induces a proinflammatory antiviral response in endometrial and vaginal epithelial cells (Patel et al., , 2018aSchaefer et al., 2005;Trifonova et al., 2009), decreased responsiveness to viral pathogens could compromise epithelial cell-mediated innate protection throughout the FRT. Whether PRR expression in general and responsiveness to TLR agonists decreases with age in the FRT is unknown. At other sites in the body, increased age is associated with decreased responsiveness to PRR stimulation (Dunston & Griffiths, 2010;Iram et al., 2012;Panda et al., 1950).

| Mucus
FRT epithelial cells produce a protective mucus layer that reduces direct contact with pathogens, such as HIV, by trapping them and preventing access to the epithelium (Lai et al., 2009;Shukair et al., 2013). Major constituents of mucus are the negatively charged glycoproteins known as mucins which form a network of protein complexes that can bind incoming pathogens. In premenopausal women, mucin (MUC) gene expression varies with menstrual status leading to changes in the overall properties of mucus including consistency and permeability (Elstein, 1978;Gipson et al., 1997;Vigil et al., 2009). Following menopause, the expression of vaginal MUC4 and MUC5AC decreases (Moncla et al., 2016) potentially reducing mucus binding capacity and its ability to interact with pathogens.
In the lower FRT of premenopausal women, vaginal mucus has an acidic pH that reduces HIV infectivity (Tyssen et al., 2018). Some studies show that postmenopausal women have increased vaginal pH compared to premenopausal women (Thurman et al., 2017), while others show no difference in pH between the two populations   (Fahey et al., 2008), but inhibits HBD2 and elafin secretion by vaginal epithelial cells (Patel et al., 2013). We showed that, due to the absence of SLPI secretion, apical secretions by endometrial epithelial cells in vitro from postmenopausal women are unable to inhibit Staphylococcus aureus growth in culture in contrast to those from premenopausal women (Fahey & Wira, 2002). Loss of antibacterial activity via decreased expression of epithelial antimicrobials could be one mechanism by which older women become more susceptible to bacterial infections.

| Antimicrobials and cytokines
Several studies have investigated how sex hormones affect antimicrobial and cytokine secretions in the FRT (Cortez et al., 2014;Fahey et al., 2008;Patel et al., 2014;Wira et al., 2010) using cervicalvaginal lavage (CVL) fluid that consists of the combined secretions of epithelial cells and immune cells from the upper and lower FRT. We and others have found changes that correlate with stage of the menstrual cycle (Keller et al., 2007;Wira et al., 2010). At midcycle (days 13-14), IL-8, Surfactant Protein A, SLPI, HBD2, α-defensins 1-3, and lactoferrin in cervical-vaginal lavage (CVL) fluids are depressed and remain so for 7-10 days (Keller et al., 2007). In contrast, total protein levels and TGFβ remained unchanged during this time. Similarly, Cortez et al. (Cortez et al., 2014) demonstrated that IL-6, MIP1α, MIP1β, TNFα, GMCSF, IFNα2, and IL-10 all decreased at midcycle compared to the proliferative and secretory phases.  Similar to other FRT cells, fibroblasts are sensitive to the presence of sex hormones, particularly in the endometrium. In premenopausal women, endometrial fibroblasts decidualize during the secretory phase of the menstrual cycle due to increasing levels of progesterone. In vitro, estradiol stimulates the secretion of hepatocyte growth factor (HGF) and stromal-derived factor-1 (SDF-1α) (Coleman et al., 2009(Coleman et al., , 2012 and potentiates the upregulation of IL-27 in response to TLR3 stimulation (Patel et al., 2018a).

| CHANG E S IN FIB ROB L A S TS INDUCED BY AG ING
The phenotypic and functional changes that FRT fibroblasts undergo following menopause with reduced exposure to sex hormones, and subsequent aging are relatively unknown. Sensitivity to sex hormones is retained in postmenopausal fibroblasts suggesting that exogenous hormones can modulate the function of FRT fibroblasts as women age (Gibson et al., 2018). Endometrial fibroblasts from perimenopausal women have an altered transcriptome compared to premenopausal women characterized by changes in expression for cytoskeleton, proliferation, and survival genes (Erikson et al., 2017).

| CHANG E S IN T-CELL D IS TRIBUTI ON AND FUN C TI ON IN THE FRT
T cells are the most abundant leukocytes in the FRT of pre-and postmenopausal women Rodriguez-Garcia et al., 2014;Wira et al., 2015). However, after menopause, T-cell populations undergo changes in distribution, phenotype, and function in a site-specific manner.

| Tissue-resident memory T cells
Particularly relevant for mucosal surfaces is the presence of tissue-

| CD8+ T cells
The proportion of CD8+ T cells increases in the endometrium after in infertility (Erlebacher, 2013a(Erlebacher, , 2013b. To prevent rejection of the semi-allogeneic blastocyst, still unknown mechanisms control T-cell function specifically in the endometrium to suppress CD8+ T-cell cytotoxic activity. Cytotoxic activity of endometrial CD8+T cells, including direct killing of allogeneic target cells, is significantly suppressed in premenopausal women compared to postmenopausal women (Rodriguez-Garcia et al., 2020;White et al., 1997). Within premenopausal women, cytotoxic activity was further suppressed during the secretory phase of the menstrual cycle, when implantation and pregnancy is likely to occur in the endometrium (Rodriguez-Garcia et al., 2020;White et al., 1997). Importantly, cytotoxic activity is uniquely regulated in the endometrium, with no effect of menstrual cycle and menopausal status on cytotoxic activity by CD8+ T cells from the endocervix or ectocervix (Rodriguez-Garcia et al., 2020;White et al., 1997).
TGFβ, produced by epithelial cells and fibroblasts (Omwandho et al., 2010;Wira & Rossoll, 2003), has been shown to suppress cytotoxic activity in animal and human experimental models, including the human endometrium (Lee & Rich, 1993;Rodriguez-Garcia et al., 2020). Interestingly, TGFβ specifically suppressed cytotoxic T-cell cytotoxic activity in the years after menopause are unknown.

| CHANG E S IN D IS TRIBUTI ON AND FUN C TI ON OF D C S AND MACROPHAG E S IN THE FRT
In addition to resident T cells, mucosal surfaces contain multiple subsets of resident DCs and macrophages essential for innate immune protection and the induction and maintenance of adaptive immune responses (Schlitzer et al., 2015). The phenotype and function of DCs and macrophages are known to be strongly influenced by the tissue environment (Schlitzer et al., 2015). In the FRT, DCs and macrophages play key roles in reproduction (Dekel et al., 2014;Gnainsky et al., 2015), and their presence in the premenopausal endometrium is regulated by sex hormone (Berbic et al., 2009;Evans & Salamonsen, 2012;Schulke et al., 2008). Therefore, as reproductive function ends, DC and macrophage presence and function in the FRT would be expected to be modified.
Diverse age-dependent effects have been described for blood DCs, including increased secretion of proinflammatory cytokines, decreased secretion of type I and III IFN, increased responses against self-antigens, and altered capacity to prime T cells . However, potential age-dependent changes in DC populations in human tissues, and particularly in the FRT, are not well understood.
Several DC subsets are present throughout the FRT, including age (Agrawal, 2017;Granot et al., 2017). Regarding phenotype, a trend toward increased maturation with age has been described in intestinal DCs (Granot et al., 2017), but whether this also applies to FRT DCs remains to be determined. PD-L1 expression is increased on DCs in endometrium and cervix from postmenopausal compared to premenopausal women (Shen et al., 2016). PD-L1 increases were specific to DCs and associated with decreased PD-L1 expression on CD8+ T cells. The potential consequences of these changes on T-cell activation and peripheral tolerance remain to be determined.

F I G U R E 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

Vagina
A functional characteristic of DCs is the induction of CD103 expression on naïve CD8+ T cells, suggesting that DCs have the potential to control TRM presence in tissues (Yu et al., 2013). This ability has been demonstrated with human lung and FRT DCs (Duluc et al., 2013;Rodriguez-Garcia et al., 2018;Yu et al., 2013). Importantly, this function is regulated by menopausal status in the endometrium, with postmenopausal DCs showing enhanced ability to induce CD103 expression on naïve CD8+ T cells when compared to premenopausal DCs (Rodriguez-Garcia et al., 2018). The mechanism responsible for CD103 upregulation on CD8+ T cells is at least partly related to TGFβ signaling in a contact-dependent manner (Rodriguez-Garcia et al., 2018;Yu et al., 2013). Interestingly, this functional modification is highly selective, as it was not associated with changes in FRT DC capacity to induce T-cell proliferation after menopause (Rodriguez-Garcia et al., 2018). Potential menopausal regulation of DC function in other FRT compartments remains unknown (Figure 4).
Macrophages constitute 10%-20% of leukocytes in the FRT, with phenotypic differences between upper and lower tract Trifonova et al., 2014). In the lower FRT, macrophages express high CD14 levels, while in the endometrium, macrophages express low levels of CD14, with a subset of endometrial macrophages expressing CD163 (Jensen et al., 2012;Quillay et al., 2015;Shen et al., 2009). While it is well known that macrophage numbers increase in the endometrium prior to menstruation (Evans & Salamonsen, 2012), little is known about changes after menopause.
An early study reported significant differences in macrophage numbers between pre-and postmenopausal women in the fallopian tubes (Safwat et al., 2008), but whether that also applies to the endometrium or lower tract, or whether macrophage functional changes occur is unknown.
Functional changes in DC and macrophage throughout the FRT with aging, and the potential consequences for immune protection and induction of mucosal adaptive responses remain unknown.
The extent to which phenotype and numbers of FRT NK cells change in the postmenopausal FRT remains unknown; however, blood NK cells undergo profound changes with aging (Hazeldine & Lord, 2013). Blood NK cell subsets change with age, with decreased CD56 BRIGHT cells, increased CD56-CD16+ cells (Solana et al., 2014), and increased CD57 expression, a marker of differentiated NK cells (Gayoso et al., 2011). The percentage and number of blood CD3-CD56+ NK cells increases with age (Le Garff-Tavernier et al., 2010;Lutz et al., 1950Lutz et al., , 2005, but is accompanied by reduced proliferation capacity  suggesting accumulation as a result of increased longevity (Zhang et al., 2007). NK cells in postmenopausal women retain their sensitivity to sex hormones, since estradiol enhances proliferation of blood NK cells (Sho et al., 2017). With respect to cytotoxicity, the effects of age are unclear in that studies report decreased (Hazeldine et al., 2012), increased (Kutza & Murasko, 1994), or no change (Almeida-Oliveira et al., 2011) in cytotoxic capacity of blood NK cells. NK cells from younger women upregulate IFNγ, MIP-1α, and IL-8 to a greater extent than cells from older women (Borrego et al., 1999;Krishnaraj & Bhooma, 1996;Mariani et al., 2001;Mariani, Pulsatelli, et al., 2002;Solana et al., 1999).

| B cells
The density and distribution of B cells varies within the premenopausal FRT, with IgA-, IgG-, or IgM-producing cells predominantly found in the vagina, ectocervix, endocervix, and fallopian tubes, but minimal numbers in the endometrium and ovary (Crowley-Nowick et al., 1995;Hurlimann et al., 1978;Kelly & Fox, 1979;Kutteh et al., ,1988Kutteh et al., , , 1998Rebello et al., 1975;. In the premenopausal endometrium, during secretory phase, B cells form the central core of endometrial lymphoid aggregates surrounded by CD8+ T cells (Yeaman et al., 1997), but are undetectable in smaller aggregates present during the proliferative phase of the menstrual cycle. In postmenopausal women, aggregates are absent and B cells sparsely distributed throughout endometrial tissue.
Endometrial secretions contain IgG and IgA, with IgG present at higher levels (Schumacher et al., 1980). IgA1 and IgA2 are present in approximately equal proportions (Kutteh et al., 1996).
Endometrial secretion of IgA peaks shortly before ovulation (Kutteh et al., 1996;Schumacher et al., 1973Schumacher et al., , 1977Schumacher et al., , 1980, while stromal IgA peaks at ovulation (Kelly & Fox, 1979). IgA and IgG levels in cervical mucus also vary with stage of the menstrual cycle and are lowest at midcycle (Schumacher et al., 1973). However, in other studies, IgA and IgG were suppressed during secretory phase (Keller et al., 2007). There was no difference in IgG and IgA levels in cervico-vaginal secretions between premenopausal, postmenopausal, and pregnant women (Jilanti & Isliker, 1977).
In postmenopausal vaginal secretions, IgG and IgA levels were reduced by twofold and 15-fold, respectively, following hysterectomy (Jilanti & Isliker, 1977), demonstrating significant endometrial contributions to FRT IgG and IgA levels.
Immunoglobulins present in FRT secretions are essential components of immune protection. IgG and IgA neutralize incoming pathogens and prevent their entry into target cells (Lamm et al., ,1978(Lamm et al., , , 1995Nedrud et al., 1987). For example, anti-HIV IgM reduces infection of DCs in cervical-vaginal explant tissues (Devito et al., 2018) while levels of anti-HIV gp160 IgG antibodies in human CVL samples correlate with anti-HIV activity and reduce HIV infection of target cells in vitro . Immunoglobulins also bind to mucus in FRT secretions via mucin proteins and trap pathogens within it. Anti-HSV-1 IgG, via its Fc component, traps HSV-1 in human cervical-vaginal mucus thus preventing contact with target cells (Wang et al., 2014). Intriguingly, while both IgA and IgG bind to cervical mucus, only IgG binds to cervical-vaginal mucus (Fahrbach et al., 2013). Vaccination at peripheral sites elicits antibody-mediated mucosal protection in the FRT. For example, vaccination against HPV16 in premenopausal women leads to increased titers of anti-HPV IgG in cervical secretions that varies with menstrual cycle stage (Nardelli-Haefliger et al., 2003). How aging affects the contribution of immunoglobulin-mediated protection in the FRT is unknown.

| CON CLUS IONS
The mucosal immune system in the human FRT has uniquely evolved to meet the challenges of an external environment as well as support new life. Across multiple anatomical compartments, mucosal immunity is precisely regulated to protect against sexually transmitted pathogens while accommodating allogeneic spermatozoa and an immunologically distinct semi-allogeneic fetus. While much is known about the mucosal immune system in the FRT during the reproductive years, little is known about the changes that occur after menopause as women age. Limited studies into innate and adaptive immune functions in the FRT following menopause indicate that immune protection by epithelial cells, stromal fibroblasts, T cells, and DC in the FRT are compromised, with limited compensation. Much remains to be learned about the impact of age following menopause on immune protection in the FRT. Understanding the impact of age on mucosal immune protection in the FRT is crucial given the challenges women face in terms of urogenital infections, exposure to sexually transmitted pathogens, and gynecological cancers that threaten the lives of women worldwide. This review emphasizes the need for additional studies to provide a foundation for the development of age-appropriate therapeutic interventions that increase protection in older women, the fastest growing segment of the population in developed countries.

ACK N OWLED G M ENTS
This study was supported by NIH grants AG064794, AI117739 (CW), and AG060801 (MR-G).

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.