The enrichment of Arg1+ILC2s and ILCregs facilitates the progression of endometriosis: A preliminary study.

Innate lymphoid cells (ILCs) are a kind of lymphocytes that reside in the tissue and have an essential function in the immune microenvironment. However, the relationship between endometriosis (EMS) and ILCs is complex and not fully understood. This study examines several groups of ILCs in the peripheral blood (PB), peritoneal fluid (PF) and endometrium of patients with EMS via flow cytometry. The study observed an increase in PB ILCs, particularly ILC2s and ILCregs subsets and Arg1+ILC2s in the EMS patients were highly activated. EMS patients had significantly higher levels of serum interleukin (IL)-10/33/25 compared to controls. We also found an elevation of Arg1+ILC2s in the PF and higher levels of ILC2s and ILCregs in ectopic endometrium compared with eutopic. Importantly, a positive correlation was observed between the enrichment of Arg1+ILC2s and ILCregs in the PB of EMS patients. The findings indicate that the involvement of Arg1+ILC2s and ILCregs fosters potentially endometriosis progression.

Involvement of impaired CD8+ mucosal-associated invariant T cells and myeloid-derived suppressor cells in polycystic ovary syndrome.

BACKGROUND: Immune dysfunction is one of the mechanisms to promote polycystic ovary syndrome (PCOS). Various immune cells have been reported to be involved in the development of PCOS. Meanwhile, the disturbance of metabolism is closely related to PCOS. The aim of this study is to explore the association of mucosal-associated invariant T (MAIT) cells and myeloid-derived suppressor cells (MDSCs) with the metabolic dysfunction in PCOS. METHODS: 68 PCOS patients and 40 controls were recruited in this study and we collected the peripheral blood of participants' during their follicular phase. The frequencies of MAIT cells and MDSCs were determined by flow cytometry after being stained with different monoclonal antibodies. And the concentrations of cytokines were determined by ELISA. RESULTS: Compared to controls with normal metabolism, the frequency of MDSCs, CD8+MAIT cells and CD38+CD8+MAIT cells were significantly decreased in PCOS patients with normal metabolism, however, proportion of CD4+MAIT cells exhibited a noticeable increase. Similar results of CD8+MAIT, CD38+CD8+MAIT cells and reduced expression of IL-17 were observed in PCOS patients with metabolic dysfunction as compared to controls with metabolic disorders. PCOS patients with excessive testosterone levels displayed significantly decreased levels of CD8+MAIT, CD38+CD8+MAIT cells, MDSCs and Mo-MDSCs as compared to PCOS patients with normal testosterone concentrations. PCOS patients with abnormal weight showed a lower level and activation of CD8+MAIT cells. On the contrary, they displayed an enrichment of CD4+MAIT cells. PCOS patients with glucose metabolic disorder displayed a remarkable dysregulation of MDSCs and Mo-MDSCs. MDSCs were positively correlated with MAIT cells. Negative correlations between the frequency of CD8+MAIT cells, CD38+CD8+MAIT cells and body mass index were revealed. CD4+MAIT cells positively correlated with BMI. Mo-MDSCs were found to be negatively related to the levels of 2hour plasma glucose and HOMA-IR index. CONCLUSION: The impairment of CD8+MAIT cells and MDSCs is involved in the metabolic dysfunction of PCOS.

Impaired myeloid-derived suppressor cells are associated with recurrent implantation failure: A case-control study.

BACKGROUND: Studies have reported that myeloid-derived suppressor cells (MDSCs) contribute to maintain pregnancy. The aim of this case-control study was to test whether there is a dysregulation of peripheral MDSCs in recurrent implantation failure (RIF). METHODS: 26 RIF patients and 30 controls were recruited. Flow cytometry was applied to characterize polymorphonuclear (PMN)-MDSCs, monocytic-MDSCs (M-MDSCs), effector T cells (Teffs) and regulatory T cells (Tregs) in blood. ELISA was used to define MDSCs correlative cytokines and chemokines in serum from all patients. RESULTS: Compared with controls, RIF patients showed significant reductions of blood PMN-MDSCs, M-MDSCs, Tregs and NO production by PMN-MDSCs, whereas the expression of ζ chain on CD4+T cell receptor (TCR) and CD8+TCR displayed a remarkable upregulation in RIF patients. Moreover, RIF patients presented a lower concentration of serum chemokine (C-C motif) ligand (CCL) 5 and transforming growth factor (TGF)-ß than those from controls. Furthermore, the level of TCR ζ chain on CD4+ and CD8+ Teffs was negatively correlated not only with the percentage of PMN-MDSCs, but also with the amount of NO produced by PMN-MDSCs. The frequency of PMN-MDSCs had positive correlations with the concentration of CCL5 and TGF-ß. CONCLUSIONS: This study indicated that the dysregulation of MDSCs might impair maternal-fetal immune balance thus resulting in RIF.

The combined action of monocytic myeloid-derived suppressor cells and mucosal-associated invariant T cells promotes the progression of cervical cancer.

One of the most common promoters of the initiation and growth of the tumor is an immune disturbance. Numerous immune cells and inflammatory factors play a role in the tumor-immune microenvironment. However, few studies have investigated the correlation between these immunological events and clinical consequences in cervical cancer. We measured the levels of numerous inflammatory mediators and frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and mucosal-associated invariant T (MAIT) cells in peripheral blood (PB) of cervical cancer patients. Cervical cancer patients showed elevated production of interleukin (IL)-18 and plasma C-C chemokine ligand (CCL) 3/5. Meanwhile, an accumulation of C-C chemokine receptor 5 (CCR5) monocytic (Mo)-MDSCs and Tregs was observed. The cervical cancer group displayed increased frequencies of CD8+ , CD4+ and highly activated CD38+ CD8+ MAIT cells, and reduction of double-negative (DN) and PD1(CD279+ ) DN MAIT cells. Importantly, it was demonstrated that MAIT cells were positively related to Mo-MDSCs. Furthermore, an elevated concentration of PD1(CD279+ ) DN MAIT cells was significantly related to increased progression-free survival of patients with cervical cancer. In conclusion, our study suggests that the combined action of Mo-MDSCs and MAIT cells might be associated with the progression of cervical cancer, and the frequency of DN MAIT cells in the peripheral blood mononuclear cells was associated with the survival benefit of patients.

Reduction of myeloid derived suppressor cells by inhibiting Notch pathway prevents the progression of endometriosis in mice model.

Growing evidence suggested that immune dysregulation is one of the crucial drivers to the development of endometriosis (EMS). Myeloid derived suppressor cells (MDSCs) represent a heterogeneous subset of immature myeloid cells, and have been reported to promote the onset and progression of EMS. Notch signaling pathway played a major role in immunological reactions. Studies have found Notch signaling pathway could regulate MDSCs. However, how the biological effects of Notch signaling pathway on MDSCs may work in EMS is still unknown. In our study, we first built an endometriosis induced mice model. Then we treated mice with DAPT, a Notch signaling pathway inhibitor, or saline. We found that the DAPT could prevent the progression of EMS. The ADAM17, Notch1, Jagged1 and Hes1 were overexpressed in EMS mice, however, when mice were treated with DAPT, the overexpression was reduced. Meanwhile, we found a lower level of MDSCs in the DAPT treated EMS mice as compared to EMS mice without DAPT, accompanied by an increase of T helper (TH) 17 cells and a decrease of regulatory T cells (Tregs). We also investigated the reactive oxygen species (ROS) in peritoneal and endometriotic cells. Our results showed that ROS level decreased in both peritoneal and endometriotic cells in the study group treated with DAPT. Overall, our study indicates for the first time that blockage of Notch signaling could lessen MDSCs and ROS, and therefore preventing the development of endometriosis.

CD4+/CD8+ mucosa-associated invariant T cells foster the development of endometriosis: a pilot study.

BACKGROUND: Immune dysregulation is one of the mechanisms to promote endometriosis (EMS). Various T cell subpopulations have been reported to play different roles in the development of EMS. The mucosa-associated invariant T cell (MAIT) is an important T cell subset in the pathogenesis of various autoimmune diseases. Evidence has indicated that there are three functionally distinct MAIT subsets: CD4+, CD8+ and CD4/CD8-/- (double negative, DN) MAIT cells. Till now, the associations between endometriosis and MAIT have not been studied. Our research investigates different MAIT subpopulations in peripheral blood (PB) and peritoneal fluid (PF) from EMS patients. METHODS: Thirty-two EMS patients and eighteen controls were included. PB and PF were collected. Tests of cytokines in plasma and PF were performed by ELISA kit. Characterisations of MAIT were done by flow cytometry. MAIT cells have been defined as CD3 + CD161 + Vα7.2+ cells. Based on CD4 and CD8 expression, they were divided into CD8+MAIT, CD4+MAIT and DN MAIT. RESULTS: Enrichments of MAIT cells, especially CD4 and CD8 MAIT subsets were found. Moreover, CD8 MAIT cells had a high activation in the EMS group. EMS patients produced higher level of IL-8/12/17 as compared to these from controls. On the contrary, control patients exhibited an impressive upregulation of DN MAIT cells, however, these DN MAIT cells from controls showed a higher expression of PD-1. Lastly, we performed the relevance analysis, and discovered that the accumulation of PB MAIT cells positively correlated with an elevated level of serum CA125 production in EMS group. CONCLUSION: These results suggest that different MAIT subsets play distinct roles in the progression of endometriosis.

CCR5/CCR5 ligand-induced myeloid-derived suppressor cells are related to the progression of endometriosis.

RESEARCH QUESTION: Immunological disorders have been reported to promote the progression of endometriosis. Several recent studies have shown that myeloid-derived suppressor cells (MDSC) drive the progression of endometriosis. The aim of this case-control study was to test whether CCR5 and its ligands drive MDSC accumulation and play a role in the progression of endometriosis. DESIGN: Thirty-six endometriosis patients and 20 controls were recruited. All subjects underwent laparoscopy. An ELISA kit was used to define CCR5 ligands in plasma and peritoneal fluid from endometriosis patients; flow cytometry was then used to characterize CCR5+MDSC in peripheral blood and peritoneal fluid. RESULTS: Data showed that endometriosis patients displayed a significantly higher production of plasma CCL3 (P = 0.046) and peritoneal fluid CCL3/5 (P = 0.042/0.036) compared with those from the uterine leiomyoma group. Furthermore, the concentrations of peritoneal fluid CCL5 were elevated in late stage patients compared with those from the uterine leiomyoma group. Accumulation of blood CCR5+Mo-MDSC was detected in endometriosis patients compared with those from both the ovarian dermoid cysts and uterine leiomyoma groups. Endometriosis patients also showed an elevation of CCR5+MDSC and CCR5+Mo-MDSC in peritoneal fluid samples compared with uterine leiomyoma samples. It was also found that enrichment of CCR5+MDSC (r = 0.6807; P < 0.0001) and CCR5+Mo-MDSC (r = 0.6893; P < 0.0001) were correlated with enhanced production of CCL5 in peritoneal fluid from endometriosis patients. CONCLUSIONS: This study showed that CCR5 and its ligands could drive the progression of endometriosis by enhancing the accumulation of MDSC. These findings might produce a promising treatment that targets CCR5+MDSC for endometriosis patients.