Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

/pdf/uterine-nk-cells-active-regulators-at-the-maternal-fetal-2a913qdunl.pdf

Uterine NK cells: active regulators at the maternal-fetal interface

Our understanding of development and function of Natural Killer (NK) cells has progressed significantly in recent years. However, exactly how uterine NK (uNK) cells develop and function is still unclear. To help investigators that are beginning to study tissue NK cells, we summarize in this review our current knowledge of the development and function of uNK cells, and what is yet to be elucidated. We compare and contrast the biology of human and mouse uNK cells in the broader context of the biology of innate lymphoid cells and with reference to peripheral NK cells. We also review how uNK cells may regulate trophoblast invasion and uterine spiral arterial remodeling in human and murine pregnancy.

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Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice

Problem

Spontaneous labor at term involves leukocyte recruitment and infiltration into the choriodecidua; yet, characterization of these leukocytes and their immunological mediators is incomplete. The purpose of this study was to characterize the immunophenotype of choriodecidual leukocytes as well as the expression of inflammatory mediators in human spontaneous parturition at term.



Method of study

Choriodecidual leukocytes were analyzed by FACS, immunohistochemistry, and RT-PCR in three different groups: (i) preterm gestation delivered for medical indications without labor; (ii) term pregnancy without labor; and (iii) term pregnancy after spontaneous labor.



Results

Two T-cell subsets of memory-like T cells (CD3+CD4+CD45RO+ and CD3+CD4−CD8−CD45RO+ cells) were identified in the choriodecidua of women who had spontaneous labor. Evidence for an extensive immune signaling network composed of chemokines (CXCL8 and CXCL10), chemokine receptors (CXCR1-3), cytokines (IL-1β and TNF-α), cell adhesion molecules, and MMP-9 was identified in these cells during spontaneous labor at term.



Conclusions

The influx of memory-like T cells in the choriodecidua and the evidence that they are active by producing chemokines and cytokines, and expressing chemokine receptors, cell adhesion molecules, and a matrix-degrading enzyme provides support for the participation of the adaptive immune system in the mechanisms of spontaneous parturition at term.

Evidence for a Role for the Adaptive Immune Response in Human Term Parturition

Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts

The hallmark of human early pregnancy is the accumulation of a unique population of Natural Killer (dNK) cells at the main maternal-fetal interface, the decidua basalis. dNK cells play a crucial role in successful placentation probably by orchestrating the invasion of trophoblast cells deep into the decidua basalis and remodeling of the maternal spiral arteries. Recent advances in the field emphasize the importance of the local microenvironment in shaping both the phenotype and the effector functions of these innate lymphoid cells. Despite slow progress in the field, ex vivo studies revealed that dNK cells sense and destroy infected cells in order to protect the fetus from invading pathogens. In this review, we will discuss key features of dNK cells during healthy pregnancy as well as their functional adaptations in limiting pathogen dissemination to the growing conceptus. The challenge is to better understand the plasticity of dNK cells in the maternal-fetal interface. Such insights would enable greater understanding of the pathogenesis in congenital infections and pregnancy disorders.

https://hal.archives-ouvertes.fr/hal-02405520/document

Features of Human Decidual NK Cells in Healthy Pregnancy and During Viral Infection.

Citation Veljkovic Vujaklija D, Gulic T, Sucic S, Nagata K, Ogawa K, Laskarin G, Saito S, Haller H, Rukavina D. First trimester pregnancy decidual natural killer cells contain and spontaneously release high quantities of granulysin. Am J Reprod Immunol 2011; 66: 363–372



Problem  Granulysin (GNLY) is a novel cytolytic protein lytic against a variety of tumor cells and microbes. The role of GNLY during pregnancy has not been extensively explored. The aim of this study is to examine GNLY expression and distribution in the first trimester pregnancy peripheral blood (PB) and decidua, the ability of decidual and PB natural killer (NK) cells to secrete GNLY spontaneously, and the role of antigen-presenting cells (APC) in the regulation of GNLY expression in decidual NK cells.



Method of study  GNLY expression was analyzed using cell permeabilization method, flow cytometry, and immunohistochemistry. GNLY secretion by purified NK cells was detected by ELISA method.



Results  GNLY is abundantly expressed at the maternal–fetal interface in the first trimester pregnancy. Decidual T lymphocytes express significantly higher levels of GNLY (58%) then PB T lymphocytes (11%). Over 85% of decidual CD56+ cells express GNLY and when cultured spontaneously release high quantities of GNLY. Decidual APC participate in the control of GNLY expression in CD56+ cells.



Conclusion  Abundant expression of GNLY in the decidual immunocompetent cells and the capacity of decidual CD56+ cells to spontaneously secrete high quantities of GNLY point to important protective and immunomodulatory role that this molecule could play at the maternal–fetal interface.

First trimester pregnancy decidual natural killer cells contain and spontaneously release high quantities of granulysin.

Granulysin expression and the interplay of granulysin and perforin at the maternal-fetal interface.

During mammal pregnancy, a sensitive balance between hormones, cytokines, humoral factors, and local cellular interactions must be established. Cytotoxic cells infiltrating the decidua are heavily equipped with cytolytic molecules, in particular perforin and granulysin. Granulysin is especially abundant in NK cells which are able to spontaneously secrete high quantities of granulysin. Besides being a potent bactericidal and tumoricidal molecule, granulysin is also found to be a chemoattractant and a proinflammatory molecule. The precise role(s) of granulysin at the maternal-fetal interface has not been elucidated yet. It is possible that it behaves as a double-edged sword simultaneously acting as an immunomodulatory and a host defense molecule protecting both the mother and the fetus from a wide spectrum of pathogens, and on the other hand, in case of an NK cell activation, acting as an effector molecule causing the apoptosis of semiallograft trophoblast cells and consequently leading to various pregnancy disorders or pregnancy loss.

/pdf/cell-death-mechanisms-at-the-maternal-fetal-interface-1h72lhch95.pdf

Cell Death Mechanisms at the Maternal-Fetal Interface: Insights into the Role of Granulysin

Background: Breast carcinoma is the most common malignant disease in the female population and one of the leading causes of death among women worldwide. One crucial hallmark of cancer is chronic inflammation where the immunosuppressive environment is dominant. The immunosuppressive environment is largely achieved by the interaction of tumor cells and infiltrating leukocytes. Summary: Usually, human macrophages and natural killer cells are involved in antitumor immunity. The therapeutic potential of this population against cancers has stimulated their study and led to the discovery of several different tumor-associated macrophages and natural killer cell subsets, each of which is endowed with different immunoregulatory functions. Both heterogeneity and plasticity of the tumor-associated macrophages and natural killer cell compartment, which are both tightly linked to the tumor microenvironment of different breast cancer types. Key Messages: The identification of specific tumor-associated macrophages and natural killer cell subsets endowed with particular functional capabilities might help monitor tumor-mediated responses in breast cancer patients. Currently, one of the most used strategies for breast cancer of newly diagnosed patients is neoadjuvant chemotherapy.

/pdf/the-role-of-innate-immunity-in-the-pathogenesis-of-breast-42ckiz1o63.pdf

Danijela Veljković Vujaklija

Papers

First trimester pregnancy decidual natural killer cells contain and spontaneously release high quantities of granulysin.

Granulysin expression and the interplay of granulysin and perforin at the maternal-fetal interface.

Cell Death Mechanisms at the Maternal-Fetal Interface: Insights into the Role of Granulysin

The Role of Innate Immunity in the Pathogenesis of Breast Cancer.

Transitory bone marrow oedema of the hip in pregnant patient with antiphospholipid syndrome: A case report