Pregnancy-induced transfer of pathogen-specific T cells from mother to fetus in mice.

Neonatal health is determined by the transfer of maternal antibodies from the mother to the fetus. Besides antibodies, maternal cells cross the placental barrier and seed into fetal organs. Contrary to maternal antibodies, maternal microchimeric cells (MMc) show a high longevity, as they can persist in the offspring until adulthood. Recent evidence highlights that MMc leukocytes promote neonatal immunity against early-life infections in mice and humans. As shown in mice, this promotion of immunity was attributable to an improved fetal immune development. Besides this indirect effect, MMc may be pathogen-specific and thus, directly clear pathogen threats in the offspring postnatally. By using ovalbumin recombinant Listeria monocytogenes (LmOVA), we here provide evidence that OVA-specific T cells are transferred from the mother to the fetus, which is associated with increased activation of T cells and a milder course of postnatal infection in the offspring. Our data highlight that maternally-derived passive immunity of the neonate is not limited to antibodies, as MMc have the potential to transfer immune memory between generations.

The 'communicatome' of pregnancy: spotlight on cellular and extravesicular chimerism.

Communication via biological mediators between mother and fetus are key to reproductive success and offspring's future health. The repertoire of mediators coding signals between mother and fetus is broad and includes soluble factors, membrane-bound particles and immune as well as non-immune cells. Based on the emergence of technological advancements over the last years, considerable progress has been made toward deciphering the "communicatome" between fetus and mother during pregnancy and even after birth. In this context, pregnancy-associated chimerism has sparked the attention among immunologists, since chimeric cells-although low in number-are maintained in the allogeneic host (mother or fetus) for years after birth. Other non-cellular structures of chimerism, e.g. extracellular vesicles (EVs), are increasingly recognized as modulators of pregnancy outcome and offspring's health. We here discuss the origin, distribution and function of pregnancy-acquired microchimerism and chimeric EVs in mother and offspring. We also highlight the pioneering concept of maternal microchimeric cell-derived EVs in offspring. Such insights expand the understanding of pregnancy-associated health or disease risks in mother and offspring.

A unique maternal and placental galectin signature upon SARS-CoV-2 infection suggests galectin-1 as a key alarmin at the maternal-fetal interface.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic imposed a risk of infection and disease in pregnant women and neonates. Successful pregnancy requires a fine-tuned regulation of the maternal immune system to accommodate the growing fetus and to protect the mother from infection. Galectins, a family of ß-galactoside-binding proteins, modulate immune and inflammatory processes and have been recognized as critical factors in reproductive orchestration, including maternal immune adaptation in pregnancy. Pregnancy-specific glycoprotein 1 (PSG1) is a recently identified gal-1 ligand at the maternal-fetal interface, which may facilitate a successful pregnancy. Several studies suggest that galectins are involved in the immune response in SARS-CoV-2-infected patients. However, the galectins and PSG1 signature upon SARS-CoV-2 infection and vaccination during pregnancy remain unclear. In the present study, we examined the maternal circulating levels of galectins (gal-1, gal-3, gal-7, and gal-9) and PSG1 in pregnant women infected with SARS-CoV-2 before vaccination or uninfected women who were vaccinated against SARS-CoV-2 and correlated their expression with different pregnancy parameters. SARS-CoV-2 infection or vaccination during pregnancy provoked an increase in maternal gal-1 circulating levels. On the other hand, levels of PSG1 were only augmented upon SARS-CoV-2 infection. A healthy pregnancy is associated with a positive correlation between gal-1 concentrations and gal-3 or gal-9; however, no correlation was observed between these lectins during SARS-CoV-2 infection. Transcriptome analysis of the placenta showed that gal-1, gal-3, and several PSG and glycoenzymes responsible for the synthesis of gal-1-binding glycotopes (such as linkage-specific N-acetyl-glucosaminyltransferases (MGATs)) are upregulated in pregnant women infected with SARS-CoV-2. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies the SARS-CoV-2 infection and vaccination in pregnancy, and they highlight a potentially significant role for gal-1 as a key pregnancy protective alarmin during virus infection.

Expansion-enhanced super-resolution radial fluctuations enable nanoscale molecular profiling of pathology specimens.

Expansion microscopy physically enlarges biological specimens to achieve nanoscale resolution using diffraction-limited microscopy systems1. However, optimal performance is usually reached using laser-based systems (for example, confocal microscopy), restricting its broad applicability in clinical pathology, as most centres have access only to light-emitting diode (LED)-based widefield systems. As a possible alternative, a computational method for image resolution enhancement, namely, super-resolution radial fluctuations (SRRF)2,3, has recently been developed. However, this method has not been explored in pathology specimens to date, because on its own, it does not achieve sufficient resolution for routine clinical use. Here, we report expansion-enhanced super-resolution radial fluctuations (ExSRRF), a simple, robust, scalable and accessible workflow that provides a resolution of up to 25 nm using LED-based widefield microscopy. ExSRRF enables molecular profiling of subcellular structures from archival formalin-fixed paraffin-embedded tissues in complex clinical and experimental specimens, including ischaemic, degenerative, neoplastic, genetic and immune-mediated disorders. Furthermore, as examples of its potential application to experimental and clinical pathology, we show that ExSRRF can be used to identify and quantify classical features of endoplasmic reticulum stress in the murine ischaemic kidney and diagnostic ultrastructural features in human kidney biopsies.

Establishment of tissue-resident immune populations in the fetus.

The immune system establishes during the prenatal period from distinct waves of stem and progenitor cells and continuously adapts to the needs and challenges of early postnatal and adult life. Fetal immune development not only lays the foundation for postnatal immunity but establishes functional populations of tissue-resident immune cells that are instrumental for fetal immune responses amidst organ growth and maturation. This review aims to discuss current knowledge about the development and function of tissue-resident immune populations during fetal life, focusing on the brain, lung, and gastrointestinal tract as sites with distinct developmental trajectories. While recent progress using system-level approaches has shed light on the fetal immune landscape, further work is required to describe precise roles of prenatal immune populations and their migration and adaptation to respective organ environments. Defining points of prenatal susceptibility to environmental challenges will support the search for potential therapeutic targets to positively impact postnatal health.

Pregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice.

Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring's developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.

Inefficient Placental Virus Replication and Absence of Neonatal Cell-Specific Immunity Upon Sars-CoV-2 Infection During Pregnancy.

Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of non-infected women at birth with SARS-CoV-2 in vitro revealed inefficient SARS-CoV-2 replication in different types of placental tissues, which provides a rationale for the low ex vivo viral expression. We further detected specific SARS-CoV-2 T cell responses in pregnant women within a few days upon infection, which was undetectable in cord blood. Our present findings confirm that vertical transmission of SARS-CoV-2 is rare, likely due to the inefficient virus replication in placental tissues. Despite the predominantly benign course of infection in most mothers and negligible risk of vertical transmission, continuous vigilance on the consequences of COVID-19 during pregnancy is required, since the maternal immune activation in response to the SARS-CoV2 infection may have long-term consequences for children's health.

Vertically transferred maternal immune cells promote neonatal immunity against early life infections.

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.