Search Results (16)

Persistent type I interferon (IFN-I) signaling compromises adaptive anti-HIV-1 T cell immunity and promotes viral reservoir persistence, yet its effects on innate lymphoid cells during chronic infection remain unclear. Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination antiretroviral therapy (cART) and IFN-I signaling blockade, we reveal IFN-I-induced dysfunction of natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s). Mechanistically, the IFN-I-CD9 axis drives NK cells toward a decidual NK cell-like phenotype, impairing their cytotoxic activity. Furthermore, IFNAR blockade rescues ILC3 functionality, which is critical for IL-17/IL-22-mediated antimicrobial defense and mucosal barrier maintenance. Our study delineates IFN-I-driven immunosuppression across innate lymphocyte compartments and proposes the targeted modulation of this pathway to enhance antiviral and mucosal immunity in HIV-1 management. Full article

Maternal–fetal tolerance mechanisms are crucial during human pregnancy to prevent the immune rejection of the embryo. A well-known mechanism blocking NK-cell cytotoxicity is the interaction of their inhibitory killer-cell immunoglobulin-like receptors (iKIR) with HLA-C molecules on the target cells. In this study, we aimed to investigate the expression of iKIRs (KIR2DL1 and KIR2DL2/3) on the matched decidual and peripheral γδT cells and the localization of HLA-C ligands throughout human pregnancy. The degranulation of γδT cells of pregnant and non-pregnant women in the presence of trophoblast cells was evaluated as well. Our results showed a higher proportion of iKIR-positive γδT cells at the maternal–fetal interface early in human pregnancy compared to the paired blood of pregnant women and full-term pregnancy decidua. In accordance, HLA-C was intensively expressed by the intermediate cytotrophoblasts and decidua-invading extravillous trophoblasts (EVTs) in early but not late pregnancy. Decidual γδT cells during early pregnancy showed higher spontaneous degranulation compared to their blood pairs, but neither decidual nor peripheral γδ T cells increased their degranulation in the presence of Sw71 EVT-like cells. The latter were unable to suppress the higher cytotoxicity of γδT cells, suggesting a complex regulatory landscape beyond NK-like activity inhibition. Full article

In approximately half of the recurrent spontaneous abortion (RSA) cases, the underlying cause is unknown. However, most unexplained miscarriages are thought to be linked to immune dysfunction. This review summarizes the current evidence regarding the immunological evaluations of patients with RSA, with potential implications for clinical research. The immune system plays a crucial role in the successful outcome of pregnancy, as it tolerates the semi-allogeneic fetus while offering protection to both the mother and fetus from pathogens. The maternal-fetal interface is the place where the crosstalk between various immune cells such as macrophages, dendritic cells, natural killer (NK) cells, and T cells takes place. An adequate balance is required between these immune cells for pregnancy to progress. In RSA, a dysregulation between these immune players is witnessed. For example, in RSA, NK cells are not increased but also undergo a change in their activity, manifested as cytotoxic decidual NK. Similarly, regulatory T cells, which are crucial for fostering a tolerant immune environment, are decreased in RSA women. Similarly, imbalances between T-helper (Th1, Th2, Th17) cell subsets have been implicated in RSA. Furthermore, the imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophage phenotypes has been documented, with studies indicating a predominance of M1 macrophages in RSA patients. Targeting immune imbalances with therapies such as immunoglobulin administration, TNF inhibitors, and anticoagulants may improve pregnancy outcomes in women with RSA. Full article

Background: Pregnancy, a complex biological phenomenon, relies on intricate maternal–fetal interactions for success. Decidual natural killer (dNK) cells and trophoblasts are pivotal in establishing immune tolerance at the maternal–fetal interface. The chemokine receptor CXCR4 plays a crucial role in NK cell development and immune tolerance during early placental development. Methods: Primary decidual immune cells from 42 women with normal pregnancies and 20 patients experiencing recurrent spontaneous abortions (RSAs) were studied. Gene transcription in NK cells was assessed using real-time polymerase chain reaction. In a co-culture system, we examined the influence of trophoblasts on CXCR4 expression in dNK cells, with subsequent analysis conducted via flow cytometry. The proportion of CXCR4⁺ NK cells was assessed using flow cytometry after co-culture with trophoblasts pre-treated with 3-MA or a p53 activator. Results: Our study confirmed a diminished presence of decidual CXCR4⁺ NK cells in RSA patients during early pregnancy. Co-culturing with a trophoblast-derived supernatant increased CXCR4 expression in dNK cells. In addition, trophoblast autophagy plays an educative role in regulating the dNK landscape via the IGF2-TP53-CXCR4 axis. Conclusion: Autophagy inhibition in trophoblasts induces an aberrant shift in the CXCR4⁺ dNK phenotype, potentially contributing to pregnancy loss. This sheds light on the nuanced behavior of dNK cells during pregnancy, offering promising therapeutic avenues to mitigate pregnancy complications. Full article

Decidual natural killer cells (dNK cells) are an essential component of the immune cells present at the maternal–foetal interface during early pregnancy, and they play a vital role in various physiological processes. Abnormalities in the ratio or function of dNK cells have been linked to recurrent miscarriages. CD96 has been previously shown to regulate NK cell function in the tumour microenvironment; however, its role and mechanism at the maternal–foetal interface remains unclear. The present study aimed to investigate the immunomodulatory role of CD96 in dNK cells and its function at the maternal–foetal interface. Immunofluorescence staining and flow cytometry were used to detect the expression of cellular markers such as CD96. Furthermore, the secretory function, adhesion-function-related molecules, and cell proliferation markers of CD96+ and CD96− dNK cells were detected using flow cytometry. In addition, we performed cell culture experiments via the magnetic bead sorting of NK cells to detect changes in the expression of the aforementioned functional molecules in dNK cells after the CD96 blockade. Furthermore, we examined the functional characteristics of dNK cells after palmitic acid treatment at a concentration of 10 μM. We also examined the changes in dNK cell function when subjected to the combined effect of palmitic acid and CD96 antagonists. The results indicated that CD96, TIGIT, CD155, and CD112 were highly expressed at the maternal–foetal interface, with dNK cells predominantly expressing CD96, whereas TIGIT was mainly expressed on T cells, and CD155 and CD112 were mainly present in metaphase stromal and trophoblast cells. CD96+ dNK cells displayed low cytotoxic activity and a high adhesion phenotype, which mediated the immunosuppressive effect on dNK cells at the maternal–foetal interface. Palmitic acid upregulated CD96 expression on the surface of dNK cells in the coculture system, inhibiting dNK cell activity and increasing their adhesion molecule expression. CD96 antagonist treatment blocked the inhibitory effect of trophoblasts on dNK cells, resulting in enhanced cytokine secretion and reduced adhesion. The results of this study provide valuable insight into the immunomodulatory role of CD96 in dNK cells and its mechanism at the maternal–foetal interface, particularly in metaphase NK cells. This study sheds light on the mechanisms of immune regulation at the maternal–foetal interface and their implications for the study of recurrent miscarriages of unknown origin. Full article

Human leukocyte antigen-G (HLA-G) is a non-classical human major histocompatibility complex (MHC-I) molecule with the membrane-bound and soluble types. HLA-G is primarily expressed by extravillous cytotrophoblast cells located at the maternal–fetal interface during pregnancy and is essential in establishing immune tolerance. This review provides a comprehensive understanding of the multiple molecular mechanisms by which HLA-G regulates the immune function of NK cells. It highlights that HLA-G binds to microRNA to suppress NK cell cytotoxicity and stimulate the secretion of growth factors to support fetal growth. The interactions between HLA-G and NK cells also activate senescence signaling, promoting spiral artery remodeling and maintaining the balance of maternal–fetal immune responses. In addition, HLA-G can inhibit the function of decidual T cells, dendritic cells, and macrophages. Overall, the interaction between trophoblast cells and immune cells mediated by HLA-G plays a crucial role in understanding immune regulation at the maternal–fetal interface and offers insights into potential treatments for pregnancy-related diseases. Full article

(1) Background: SARS-CoV-2 infection during pregnancy could determine important maternal and fetal complications. We aimed to prospectively assess placental immunohistochemical changes, immunophenotyping alterations, and pregnancy outcomes in a cohort of patients with COVID-19; (2) Methods: 52 pregnant patients admitted to a tertiary maternity center between October 2020 and November 2021 were segregated into two equal groups, depending on the presence of SARS-CoV-2 infection. Blood samples, fragments of umbilical cord, amniotic membranes, and placental along with clinical data were collected. Descriptive statistics and a conditional logistic regression model were used for data analysis; (3) Results: Adverse pregnancy outcomes such as preterm labor and neonatal intensive care unit admission did not significantly differ between groups. The immunophenotyping analysis indicated that patients with moderate–severe forms of COVID-19 had a significantly reduced population of T lymphocytes, CD4+ T cells, CD8+ T cells (only numeric), CD4+/CD8+ index, B lymphocytes, and natural killer (NK) cells. Our immunohistochemistry analysis of tissue samples failed to demonstrate positivity for CD19, CD3, CD4, CD8, and CD56 markers; (4) Conclusions: Immunophenotyping analysis could be useful for risk stratification of pregnant patients, while further studies are needed to determine the extent of immunological decidual response in patients with various forms of COVID-19. Full article

Ovarian stimulation is associated with an increased incidence of abnormal placentation. Uterine natural killer (uNK) cells are the major subpopulation of decidual immune cells, which are crucial for placentation. In a previous study, we found that ovarian stimulation impairs uNK cell density on gestation day (GD) 8.5 in mice. However, it was not clear how ovarian stimulation led to a reduction in the density of uNK cells. In this study, we constructed two mouse models, an in vitro mouse embryo transfer model and an estrogen-stimulated mouse model. We used HE and PAS glycogen staining, immunohistochemical techniques, q-PCR, Western blot, and flow cytometry to analyze the mouse decidua and placenta, and the results showed that SO resulted in a fetal weight reduction, abnormal placental morphology, decreased placental vascular density, and abnormal density and function of uNK cells. Our results suggest that ovarian stimulation resulted in aberrant estrogen signaling and may contribute to the disorder of uNK cells caused by ovarian stimulation. Together, these results provide new insights into the mechanisms of aberrant maternal endocrine environments and abnormal placentation. Full article

Recurrent pregnancy losses (RPL) is a common reproductive disorder with various underlying etiologies. In recent years, rapid progress has been made in exploring the immunological mechanisms for RPL. A propensity toward Th2 over Th1 and regulatory T (Treg) over Th17 immune responses may be advantageous for reproductive success. In women with RPL and animals prone to abortion, an inordinate expression of cytokines associated with implantation and early embryo development is present in the endometrium or decidua secreted from immune and non-immune cells. Hence, an adverse cytokine milieu at the maternal-fetal interface assaults immunological tolerance, leading to fetal rejection. Similar to T cells, NK cells can be categorized based on the characteristics of cytokines they secrete. Decidual NK (dNK) cells of RPL patients exhibited an increased NK1/NK2 ratio (IFN-γ/IL-4 producing NK cell ratios), leading to pro-inflammatory cytokine milieu and increased NK cell cytotoxicity. Genetic polymorphism may be the underlying etiologies for Th1 and Th17 propensity since it alters cytokine production. In addition, various hormones participate in cytokine regulations, including progesterone and estrogen, controlling cytokine balance in favor of the Th2 type. Consequently, the intricate regulation of cytokines and hormones may prevent the RPL of immune etiologies. Local or systemic administration of cytokines or their antagonists might help maintain adequate cytokine milieu, favoring Th2 over Th1 response or Treg over Th17 immune response in women with RPL. Herein, we provided an updated comprehensive review regarding the immune-regulatory role of pro- and anti-inflammatory cytokines in RPL. Understanding the roles of cytokines involved in RPL might significantly advance the early diagnosis, monitoring, and treatment of RPL. Full article

A high number of leucocytes reside in the human endometrium and are distributed differentially during the menstrual cycle and pregnancy. During early pregnancy, decidual natural killer (dNK) cells are the most common type of natural killer (NK) cells in the uterus. The increase in the number of uterine NK (uNK) cells during the mid-secretory phase of the menstrual cycle, followed by further increase of dNK cells in early pregnancy, has heightened interest in their involvement during pregnancy. Extensive research has revealed various roles of dNK cells during pregnancy including the formation of new blood vessels, migration of trophoblasts, and immunological tolerance. The present review article is focused on the significance of NK cells during pregnancy and their role in pregnancy-related diseases. The article will provide an in-depth review of cellular and molecular interactions during pregnancy and related disorders, with NK cells playing a pivotal role. Moreover, this study will help researchers to understand the physiology of normal pregnancy and related complications with respect to NK cells, so that future research work can be designed to alleviate the complications. Full article

In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56⁺) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA—a methylation agent—for 7 days in hypoxia (94% N₂, 1% O₂, 5% CO₂). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN–γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients’ supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade. Full article

Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFβ, acquire the CD56^brightCD9⁺CD49a⁺ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFβ action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFβ. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFβ induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFβ in increasing the percentage of CD56^bright, CD16⁻, CD9⁺ and CD49a⁺, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFβ and decreased the TGFβ upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFβ and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a⁺ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFβ-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFβ stimulation represents a model to prove TIMP’s new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic–therapeutic roles. Full article

Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young. Full article

NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology. Full article

The pathogenesis of many serious diseases, including cancer, is closely related to disturbances in the angiogenesis process. Angiogenesis is essential for the progression of tumor growth and metastasis. The tumor microenvironment (TME) has immunosuppressive properties, which contribute to tumor expansion and angiogenesis. Similarly, the uterine microenvironment (UME) exerts a tolerogenic (immunosuppressive) and proangiogenic effect on its cells, promoting implantation and development of the embryo and placenta. In the TME and UME natural killer (NK) cells, which otherwise are capable of killing target cells autonomously, enter a state of reduced cytotoxicity or anergy. Both TME and UME are rich with factors (e.g., TGF-β, glycodelin, hypoxia), which support a conversion of NK cells to the low/non-cytotoxic, proangiogenic CD56^brightCD16^low phenotype. It is plausible that the phenomenon of acquiring proangiogenic and low cytotoxic features by NK cells is not only limited to cancer but is a common feature of different angiogenesis-dependent diseases (ADDs). In this review, we will discuss the role of NK cells in angiogenesis disturbances associated with cancer and other selected ADDs. Expanding the knowledge of the mechanisms responsible for angiogenesis and its disorders contributes to a better understanding of ADDs and may have therapeutic implications. Full article