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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 117-123

Roles of regulatory T Cells in pathogenesis of endometriosis

Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR; Laboratory for Reproductive Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital and Institute of Obstetrics and Gynecology, IRD, Fudan University Shanghai Medical College, Shanghai, China

Date of Submission06-Jan-2019
Date of Web Publication9-Jul-2019

Correspondence Address:
Prof. Da-Jin Li
2nd Floor, Building 2, Lane 1326, Pingliang Road, Yangpu District, Shanghai 200082
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.262392

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Numerous studies have shown aberrant immune cell function in endometriosis, including T cells, B cells, natural killer cells, and macrophages (Mφ). These alterations are thought to be induced by various mechanisms that promote the disease. Regulatory T cells (Tregs) may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments, permitting their survival. Tregs differentiate during the development of endometriosis, which confer immunosuppression or play other roles in disease progression. In this review, we provide an overview of the regulation and roles of Tregs in endometriosis. These data provide further scientific evidence for the altered immune response in endometriosis, which could be a potential target in the treatment of endometriosis. This review could create new diagnostic strategies and effective immune-targeted therapies for this highly prevalent disease. Recent progress in the field indicates that these goals may be achieved in the future.

Keywords: Endometrial Stromal Cells; Endometriosis; Fibrinogen-Like Protein 2; Regulatory T Cells

How to cite this article:
Hou XX, Wang XQ, Li DJ. Roles of regulatory T Cells in pathogenesis of endometriosis. Reprod Dev Med 2019;3:117-23

How to cite this URL:
Hou XX, Wang XQ, Li DJ. Roles of regulatory T Cells in pathogenesis of endometriosis. Reprod Dev Med [serial online] 2019 [cited 2020 Jul 14];3:117-23. Available from: http://www.repdevmed.org/text.asp?2019/3/2/117/262392

Xin-Xin Hou and Xiao-Qiu Wang equally contributed to this article.

  Introduction Top

Endometriosis is one of the most common gynecological disorders and shows a great variability across affected individuals. Defined as the implantation and growth of endometrial tissue outside the uterus cavity,[1] this disease affects approximately 6%–10% in women of fertile age.[1],[2] Despite studies that have been conducted for understanding the pathogenesis of this disease, the origin and etiology of endometriosis remain unclear. The main symptoms of endometriosis are pelvic pain, dysmenorrhea, dyspareunia, infertility, and menstrual irregularities.[3] Unfortunately, the current medical treatment of the endometriotic implants by surgery or medication often provides only temporary relief and is associated with a high recurrence rate after treatment ends, which leads to an immense emotional and financial burden to those suffering from this disease.[1],[4]

Numerous theories have been proposed to explain the histogenesis of endometriosis. These include the generally accepted transplantation theory initially proposed by Sampson in the 1920s.[5] This theory is based on the assumption that endometriosis is caused by the seeding or implantation of endometrial cells by transtubal regurgitation during menstruation.[5] Nevertheless, although retrograde menstruation is a common phenomenon in most women with regular menstruation, it does not correlate with the prevalence of endometriosis.[6] Therefore, investigations involving the pathophysiology of this disorder based on genetic, hormonal, immune, and inherent endometrial changes may provide insights into the development of the disease. Accumulating evidence has shown that the immune system participates in the peritoneal cavity homeostasis, and modifications of its function create a microenvironment, which may facilitate the progression of endometriosis.[7],[8] CD4+ CD25+ regulatory T cells (Tregs) play an important role in maintaining immune homeostasis. The proportion of Tregs is significantly higher in the peritoneal fluid samples of patients with endometriosis than in those of control women[9],[10] and Wei et al. found that it increases as endometriosis progresses.[11] However, how Tregs (both natural and adaptive) differentiate, confer suppression, or play other roles in the development of endometriosis is poorly understood. To better understand the immunopathological mechanisms in endometriosis, we focus on the functional regulation and potential roles of Tregs in this mysterious condition.

  Endometriosis Is an Immune Disease Top

Although the pathogenesis of endometriosis remains elusive, numerous investigations indicate that disturbances in the immune response are fundamental to its etiology and pathogenesis.[12],[13],[14] Clearly, the immune system is involved in endometriosis. However, it is not clear whether this involvement is a primary response leading to the initiation, promotion, and progression of the disease or a secondary response to the ectopic endometrial growth in an attempt to restore homeostasis. Emerging evidence has shown that endometriosis is associated with disturbed local and systemic immune responses. These may include increased levels of activated peritoneal macrophages (Mφ), abnormal T and B lymphocyte activation, reduced natural killer (NK) cell activity, as well as various proinflammatory and angioregulatory cytokines [Figure 1].[15]
Figure 1: Altered immune cells populations in endometriotic milieu. A variety of immune cells such as macrophages, NK cells, and T lymphocytes have been demonstrated to be present in endometriotic lesions. The number and function of these cells have changed. The macrophage polarization toward an M2 phenotype. NK cells and CD8+ T cells have decreased cytotoxicity. There is a shifting of Th1 cells to Th2 cells, an increasing number of IL-10+ Th17 cells and Tregs with associated cytokines changes. The abnormal immune microenvironment may potentiate the development of the disease. NK: Natural killer; IL: Interleukin; Th17: Type 17 T helper; Tregs: Regulatory T cells.

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M2 Mφ polarization

Mφ is the major immune cell population in the peritoneal fluid and eliminates endometrial tissues deposited via retrograde menstruation.[16],[17],[18] Even though the number of peritoneal Mφ has been shown to be increased in peritoneal cavity in endometriosis compared to that in a disease-free peritoneum, their phagocytic capacity and debris uptake capacity has been shown to be decreased.[7],[19] More specifically, it is possible to identify two different polarized subclasses of Mφ (classically activated Mφ or M1 Mφ and alternatively activated Mφ or M2 Mφ) that describe a continuum of diverse functional states.[20],[21] Recent studies have demonstrated that there is a shift toward M2 Mφ in endometriosis, which might, in turn, cause an increase in the local production of factors promoting angiogenesis and implantation of endometrial cells.[22],[23],[24]

Reduced natural killer cells and T cell cytotoxicity

Defects of other cell types within the innate immune system, such as NK cells, may also affect the clearance of refluxed endometrial cells in endometriosis. Most studies indicate that NK cells from endometriosis display reduced cytotoxicity resulting from an increased expression of killer inhibitory receptors (KIRs) [Figure 1].[25],[26],[27],[28] Finally, the cytotoxicity of T cells was also reduced in women with endometriosis, and the peritoneal fluid of women with this disease may contribute to the survival and growth of displaced endometrium [Figure 1].[29],[30] In patients with endometriosis, there is a possible shift toward T helper 2 (Th2) immune response, as demonstrated by the increase in cytokine characteristic of this pattern;[13] change in the Th1/Th2 cell ratio might play an important role in the pathogenesis of endometriosis [Figure 1]. The continued ability of these cells to produce proinflammatory cytokines may mediate the recruitment of additional inflammatory immune cells to the sites of peritoneal disease, which may further exacerbate an excessive inflammatory microenvironment.

The roles of type 17 T helper cells and regulatory T cells

In addition, type 17 T helper (Th17) cells and Tregs have a suspected, though not well-elucidated, role in the pathogenesis of endometriosis.[2] We have found that interleukin (IL)-27 triggers Th17 cells to produce IL-10 via a c-Maf/RORγt/Blimp-1 signal to promote the rapid growth and implantation of ectopic lesions.[31] Recently, a growing amount of information strongly supports the roles of Tregs in the development of endometriosis due to their potential ability in regulation and suppression of inflammatory responses and angiogenesis [Figure 1].

  Regulatory T Cells: Phenotype and Differentiation Top

The discovery of Tregs and the elucidation of their roles in the regulation of immune responses and in the maintenance of immune tolerance have led to new insights in immunology. Markers commonly used to define human Tregs include high expression of CD25, forkhead box P3 (Foxp3) positivity, and low expression/negativity for CD127.[32],[33] According to the origin of Tregs, they can be divided into thymus-derived Tregs (tTregs) and peripheral induced Tregs (pTregs).[34] Naturally occurring tTregs express the lineage-specific transcription factor Foxp3, which is required for their development, homeostasis, and function.[35],[36],[37] Recently, neuropilin 1 (Nrp1) and Helios were reported to be specific markers for this population [Figure 2].[38],[39],[40] However, it should be noted that Nrp1 and Helios on Tregs can be changed under a potent proinflammatory condition. Therefore, local homeostasis should be taken into account when distinguishing Tregs on the basis of Nrp1 and Helios expression.[41],[42] In addition to thymus-generated Tregs, peripheral orin vitro non-Tregs can convert to Tregs under cytokine stimulation or chronic antigen stimulation (pTregs).[34],[43] Depending on the stimulus such as transforming growth factor β (TGF-β), IL-10, and IL-35, non-Tregs can develop into a subpopulation of suppressive inducible Tregs.[37],[44],[45],[46] Furthermore, a series of recent reports have led to the current understanding of tissue- and inflammation-specific Tregs.[47],[48],[49],[50] Therefore, Tregs exhibit phenotypical and functional differences in terms of transcriptional factors, surface markers, T cell receptor (TCR) repertoire, cytokine production, and signals required for their differentiation.
Figure 2: Tregs in endometriotic milieu. Tregs play an important role in endometriosis in various ways. Suppression of local immune responses by Tregs-mediated mechanism could underlie deficient clearing of ectopic endometrial cells. The crosstalk between Tregs and ectopic endometrial cells not only enhances the immune suppression of Tregs, but also promotes the survival, invasion, and angiogenesis of ectopic endometrial cells. Tregs: Regulatory T cells.

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  Molecular Mechanisms of Regulatory T Cell-Mediated Immunosuppression Top

In the past few years, there has been significant progress in defining the effector molecules that Tregs use to mediate their regulatory ability. Based on their molecular characterization and function, effector molecules of Tregs can be classified into four groups: immunosuppressive cytokines, molecules involved in metabolic disruption, cytolytic molecules, and membrane-associated molecules that downregulate the activation of effector T cells.[51],[52] Secretion of inhibitory cytokines has been proposed as a major pathway by which Tregs exert their function. Among these inhibitory cytokines, TGF-β and IL-10 have been reported as key mediators of Tregs suppression. In addition, the inhibitory cytokine IL-35 and lymphocyte activation gene-3 have been described as a potent suppressive molecule of Tregs [Figure 2].[52],[53] Several Tregs effector molecules are involved in the metabolic disruption of the effector cell or target cell, including the inhibitory second messenger cyclic AMP (cAMP). cAMP is transferred by Tregs into target cells through membrane gap junctions. Recently, studies have described the unique activity of CD39 and CD73 expressed predominately on the surface of Tregs. They catalyze the generation of pericellular adenosine that delivers a negative signal to effector cells by interaction with the adenosine receptor 2A, contributing to Tregs-mediated immunosuppression [Figure 2].[52],[54] Tregs can also release cytolytic molecules, such as granzyme A/B, perforin, and galectin 1 to kill effector cells [Figure 2]. The expression of a number of inhibitory membrane-associated molecules has also been implicated in Tregs-mediated suppression. An example of such molecule would be cytotoxic T lymphocyte antigen 4 (CTLA-4), which mediates its activities through interaction with the costimulatory molecules CD80 and CD86 on antigen-presenting cells, leading to downregulation of the maturation markers, subsequently suppressing T cell activation [Figure 2].

Recent investigations have suggested that fibrinogen-like protein 2 (FGL2) is a new effector molecule of Tregs. Tregs have increased FGL 2 gene transcription by analysis of gene expression profile. A study by Fontenot et al. has also detected high expression of FGL2 in Tregs isolated from wild-type (WT) Foxp3gfp mice and IL-2-/- mice.[55] Zheng et al. showed a positive correlation of Foxp3 to FGL2 expression.[56] In addition to CD4+ CD25+ Tregs, other subsets of Tregs have also been found to express high levels of FGL2.[57] Recombinant FGL2 inhibits T cell proliferation in response to anti-CD3, anti-CD28, and alloantigen stimulation.[58] Tregs from FGL2-/- mice are less effective in suppressing the proliferation of WT T cells, and a polyclonal anti-FGL2 completely blocked the suppressive activity of Tregs in a dose-dependent manner.[59] Moreover, recombinant FGL2 binds to dendritic cells (DCs) via the inhibitory FcγRIIB. Treatment of DCs from wild-type mice with FGL2 results in decreased expression of CD80 and CD86, whereas FGL2 treatment had no inhibitory effect on DCs from FcγRIIB-deficient mice.[59] FGL2 also polarized allogeneic T cell responses toward a Th2 cytokine profile with increased production of IL-10 and IL-4. It also decreased secretion of Th1 and Th17 cytokines, including interferon-γ and IL-17A.[60] Taken together, these studies indicate that FGL2 may act as an immunoregulatory cytokine of Tregs. Additional studies are still required in order to further define the exact roles of FGL2 in Tregs-mediated suppression, leading to development of novel therapeutic approaches for the treatment of a wide range of immune-associated diseases.

  The Functional Regulation of Regulatory T Cells and Its Roles in Endometriosis Top

Immune response and immune regulation in endometriosis appear to be highly complicated, and recent studies on the roles of Tregs in endometriosis have opened up new possibilities for future research.

The aberrant expression of regulatory T cells in eutopic endometrium

Berbic et al.[61] reported that Foxp3+ Tregs were highly upregulated in the eutopic endometrium of patients with endometriosis during the secretory phase of the menstrual cycle. At this time, their expression, however, was significantly downregulated in women without endometriosis. In disease-free women, Tregs are most prominent during the proliferative phase, while their number is significantly reduced during the secretory phase of the menstrual cycle. However, in women with endometriosis, Tregs remain abundant within the endometrium during the secretory phase, which could be associated with the pathogenesis of advanced endometriosis.[62] It was proposed that the preserved Tregs that are seen in women with endometriosis decrease the ability of newly recruited immune cell populations to effectively recognize and target endometrial antigens during menstruation. This would allow survival and implantation of shed endometrial cells. Foxp3 expression was higher in deep rectosigmoid endometriosis lesions (one of the more aggressive types of the disease) than in eutopic endometrium. Moreover, eutopic endometrium Foxp3 expression of women with endometriosis was associated with chronic pelvic pain.[63] Foxp3 mRNA expression was significantly higher in the group of infertile patients with endometriosis when compared with the control group. It was also significantly higher in patients with advanced endometriosis when compared with both mild endometriosis and control.[62] The aberrant increase of Tregs in eutopic endometrium may have a negative effect on fertility.[64]

The aberrant expression of regulatory T cells in ectopic milieu

Similarly, suppression of local immune responses by Tregs-mediated mechanism could underlie deficient clearing of ectopic tissues within the peritoneal microenvironment as discussed above. We and other groups have reported the presence of Tregs in ectopic endometrial tissue from patients with endometriosis. The ovarian endometriosis tissue samples were characterized by an overexpression of Foxp3 mRNA in comparison to normal endometrial tissue.[61],[65] Using the induced nonhuman primate model of endometriosis, Braundmeier et al. reported higher levels of Foxp3 transcript and an increased abundance of Foxp3-positive cells in ectopic lesions, indicative of immune tolerance.[66] In addition, the number of Tregs is significantly increased in peritoneal fluid of women with endometriosis,[9],[10],[11] suggesting that Tregs may play a part in the immunopathogenesis of endometriosis responsible for abrogated local cellular immune responses. However, the mechanisms behind the increase in the number of Tregs in the peritoneal fluid of women with endometriosis and the roles of Tregs in the progression of endometriosis are still not fully clarified.

The presence of regulatory T cells in peripheral blood of endometriosis patients

Although animal experiments have shown that the induction of endometriosis resulted in a dramatic and rapid decrease in both naturally occurring Tregs and adaptive Tregs in the peripheral circulation and endometrium,[64] no clear conclusions could be obtained about the involvement of Tregs in endometriosis when peripheral blood was analyzed in women. Slabe et al. found that, in nonendometriosis control women, the concentration of Tregs remained at stable levels in peripheral blood at different stages of the menstrual cycle. In contrast, there was a significant increase in the concentration of Tregs in the secretory phase in the endometriosis patients when compared with the proliferative phase and to the group without the disease in the secretory phase.[30] While Olkowska-Truchanowicz et al. showed the percentage of Tregs was significantly decreased in the peripheral blood of women with ovarian endometriosis compared with control women,[10] Takamura et al. indicated that there was no significant difference in the percentage of Tregs in the peripheral blood of women with endometriosis when compared to the control group.[67]

Chemokines and indoleamine-2,3-dioxygenase regulate regulatory T cells function to participate in the pathogenesis of endometriosis

In our previous study, we showed that the percentage of CD4+ Foxp3+ T cells in peritoneal fluid was positively correlated with the progression of endometriosis.[68] The upregulation of TECK in endometriotic-associated cells, such as endometrial stromal cells (ESCs) and Mφ, promotes Tregs differentiation, increases its IL-10 and TGF-β production, decreases FasL and Fas expression, and further inhibits Tregs apoptosis. The upregulation of TECK also increases CD73 expression and enhances the suppressive effect of Tregs on the CD4+ CD25 effector T cells. In turn, these educated Tregs stimulate ESC proliferation and invasion in IL-10, TGF-β, and CD73-dependent or- independent manners. The integral effects of these signaling molecules create an immune-tolerant microenvironment that promotes ESC survival and invasion, which leads to the development of endometriosis [Figure 2].[68]

The estrogen-indoleamine 2,3-dioxygenase 1 (IDO1)-mannose receptor C, type 2 (MRC2) axis participates in the differentiation and function of Tregs and is involved in the development of endometriosis. Therefore, blockage of IDO1 in the ectopic lesion, which does not influence physiological functions of estrogen, may be considered a potential therapy for endometriosis [Figure 2].[11] Our recent research revealed that ESC-monocyte (Mo) coculture produced significantly higher levels of C-C motif chemokine ligand (CCL) 22 and CCL17. Our studies also indicated that estradiol (E2) or progesterone (P) further promoted this upregulation, demonstrating stronger chemotaxis on Tregs.[69] The Treg-ESC-Mo coculture treated with E2 andPcould enhance the immunosuppression of Tregs. ESC-Mo coculture also stimulated TGF-β1 secretion by Tregs and significantly promoted proinflammatory cytokines IL-1β and TNF-α secretion. TGF-β1 and IL-1β or TNF-α could synergistically promote IL-8 and vascular endothelial growth factor expression in ESC, which stimulated the angiogenesis of human umbilical vein endothelial cells. Therefore, our research indicates that the high levels of CCL17 and CCL22 cause the recruitment of Tregs, upregulate the immunosuppression of Tregs, and, in turn, may promote angiogenesis in endometrial cells in synergy with proinflammatory cytokines [Figure 2].[69]

Moreover, in our recent study, we have demonstrated that the Tregs effector molecule FGL2 can not only contribute to Treg-cell-mediated immune suppression, but also selectively facilitate Th2 and M2 Mφ polarization (unpublished data). This may account, at least in part, for the Th2 immune bias in the endometriotic milieu and may serve as a new therapeutic target (unpublished data). Whether FGL2 may associate with tissue- and inflammation type-specific Tregs in peritoneal fluid or endometriotic milieu needs further efforts to fully understand. Preimplantation factor (PIF) is expressed in the epithelial ectopic cells in close proximity to Tregs. Tregs interacts with PIF-expressing epithelial cells and could modulate epithelial ectopic cells viability,[70] which may be another way to involve in the development of endometriosis.

Regulatory T cells-targeted therapy in endometriosis

Considering the important role of Tregs in endometriosis, targeting Tregs may be an effective therapy. Utilizing poly (lactic-co-glycolic acid) as protein delivery vehicles encapsulate CTLA-4-antibody (anti-CTLA-4), which is essential for CD4+ CD25+ Tregs suppressive function exposed a superior potential for inhibiting endometriosis progress in a mouse model than single anti-CTLA-4. PLGA/anti-CTLA-4 had a better suppressive activity to IL-10 and TGF-β secreted by CD4+ CD25+ Tregs. Therefore, PLGA/anti-CTLA-4 may be a potential strategy for endometriosis therapy by targeting Tregs.[71]

  Effect of Hormonal Alterations on Regulatory T Cells Top

Endometriosis is considered as an estrogen-dependent disease.[72] Endocrine and immune systems are among the most essential regulators of endometrial physiology, and immune-endocrine interactions are likely to be involved in the pathogenesis of endometriosis. Estrogen is considered to be involved in a wide range of autoimmune diseases and thought to be responsible for the increased prevalence of these diseases among females. It has notable effects on immunity and inflammatory conditions.[73] In this regard, emerging information suggests that Tregs are indirectly regulated by ovarian steroid hormones. Experimental animal studies showed that the CD4+ CD25+ Tregs and Foxp3 mRNA and protein expression were significantly increased in pregnant mice and mice treated with exogenous estrogen in vivo.[74] These results confirm that estrogen can increase the number of CD4+ CD25+ Tregs and upregulate the expression of Foxp3 mRNA. Moreover, estrogen promoted the differentiation of Tregs by elevating IDO1 expression in the ectopic lesion.[11] Progesterone is another hormone that should be considered in endometriosis, which provides key immunosuppressive actions within the reproductive tract. In addition, the altered peritoneal microenvironment in women with endometriosis is associated with progesterone resistance,[1] therefore, progesterone resistance is one of the immunopathological mechanisms of endometriosis. However, it remains to be determined how the trafficking and function of various interactive immune cell populations is affected by progesterone. A complete understanding of the immune–endocrine interactions will be helpful for future development of innovative therapies for endometriosis and other reproductive diseases.

  Conclusions Top

Immune response and regulation in endometriosis have opened new avenues for future research in this field. As noted above, Tregs may play a key role in decreasing the ability of newly recruited immune cell populations to effectively target shed endometrial fragments. Tregs may also function to downregulate the ability of mature DCs to effectively present endometrial antigens, accounting for survival and implantation of viable fragments in the ectopic milieu. Under normal conditions, shed endometrial cells may be channeled into the regional lymph tissue for destruction. However, the failure of the immune system to render these fragments in endometriosis may assist their survival and subsequent implantation at ectopic sites. In addition, Tregs may contribute to the development of the disease through synergy with proinflammatory cytokines or interaction with ectopic epithelial cells. This suggests that Tregs may play an important role in the onset and development of the disease by various mechanisms. Tregs may thus be a potential target in the treatment of endometriosis. These studies should help understand more clearly the pathogenesis of endometriosis. Further thorough understanding of the roles of specific immune cell responses and the roles of Tregs-induced immune modulation in endometriosis will possibly create new diagnostic strategies and effective immune-targeted therapies for this highly prevalent disease.

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