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The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface.

ABSTRACT: To establish a healthy pregnancy, maternal immune cells must tolerate fetal allo-antigens and remain competent to respond to infections both systemically and in placental tissues. Extravillous trophoblasts (EVT) are the most invasive cells of extra-embryonic origin to invade uterine tissues and express polymorphic Human Leucocyte Antigen-C (HLA-C) of both maternal and paternal origin. Thus, HLA-C is a key molecule that can elicit allogeneic immune responses by maternal T and NK cells and for which maternal-fetal immune tolerance needs to be established. HLA-C is also the only classical MHC molecule expressed by EVT that can present a wide variety of peptides to maternal memory T cells and establish protective immunity. The expression of paternal HLA-C by EVT provides a target for maternal NK and T cells, whereas HLA-C expression levels may influence how this response is shaped. This dual function of HLA-C requires tight transcriptional regulation of its expression to balance induction of tolerance and immunity. Here, we critically review new insights into: (i) the mechanisms controlling expression of HLA-C by EVT, (ii) the mechanisms by which decidual NK cells, effector T cells and regulatory T cells recognize HLA-C allo-antigens, and (iii) immune recognition of pathogen derived antigens in context of HLA-C.

SUBMITTER: Papuchova H

PROVIDER: S-EPMC6913657 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface.

Papúchová Henrieta H Meissner Torsten B TB Li Qin Q Strominger Jack L JL Tilburgs Tamara T

Frontiers in immunology 20191209

To establish a healthy pregnancy, maternal immune cells must tolerate fetal allo-antigens and remain competent to respond to infections both systemically and in placental tissues. Extravillous trophoblasts (EVT) are the most invasive cells of extra-embryonic origin to invade uterine tissues and express polymorphic Human Leucocyte Antigen-C (HLA-C) of both maternal and paternal origin. Thus, HLA-C is a key molecule that can elicit allogeneic immune responses by maternal T and NK cells and for whi ...[more]

PMID: 31921098

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Project description:BackgroundPreeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed.MethodsSingle-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte.ResultsA total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation.ConclusionsWe revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target.

Project description:Background and objectiveThe establishment of maternal-fetal interface immune tolerance is essential for successful pregnancy. Studies have shown that spontaneous abortion, recurrent abortion, and fetal growth restriction are related to maternal-fetal interface immune dysfunction. Preeclampsia is an idiopathic condition related to pregnancy which manifests as hypertension, proteinuria, and other target organ damage after 20 weeks of gestation. Although the etiology of preeclampsia is still unknown, its pathogenesis is thought to be related to genetics, environment, and metabolism. In recent years, more and more studies have been conducted on the mechanism of immune tolerance at the maternal-fetal interface and the relationship between immune dysregulation and the pathogenesis of preeclampsia. This paper summarizes the latest studies on this topic in order to find new insights into the pathogenesis of preeclampsia and make a reflection on clinical diagnosis and treatment in different phenotype of preeclampsia.MethodsThe research and latest progress published from 2000 to December 2021 on the relationship between maternal-fetal interface immune tolerance and preeclampsia were broadly retrieved and researched using PubMed and Web of Science databases.Key content and findingsThe mechanism of natural killer cells (NK cells) and macrophages at the maternal-fetal interface in immune tolerance, as well as their cytotoxicity and cytokine secretion dysfunction, may be related to the pathogenesis of preeclampsia. The expression of nonclassical type I human leukocyte antigen (HLA) on extravillous trophoblast (EVT) cell were down-regulated in decidua of preeclampsia, which may induce increase EVT death caused by activating of cytotoxic NK cell. In addition, genetic polymorphism of nonclassical type I HLA on the EVT cell membrane may be related to the pathogenesis of preeclampsia, although this is likely to be a combination of 3 nonclassical type I HLA genotypes and requires sequencing to verify.ConclusionsWe demonstrated how the maternal-fetal interface immune dysfunction contribute to the pathogenesis of preeclampsia, further study and clinical trial based on this theory of pathogenesis may reveal new immune treatment method of preeclampsia.

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The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface.

Publications

The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface.

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