Search

Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.

The junctional adhesion molecule (JAM)-B, a member of the immunoglobulin superfamily, is involved in stabilization of interendothelial cell-cell contacts, formation of vascular tubes, homeostasis of stem cell niches and promotion of leukocyte adhesion and transmigration. In the human placenta, JAM-B protein is abundant and mRNA transcripts are enriched in first-trimester extravillous trophoblast in comparison to the villous trophoblast. We here aimed to elucidate the yet unexplored spatio-temporal expression of JAM-B in the mouse placenta. We investigated and semi-quantified JAM-B protein expression by immunohistochemistry in early post-implantation si tes and in mid- to late gestation placentae of various murine mating combinations. Surprisingly, the endothelium of the placental labyrinth was devoid of JAM-B expression. JAM-B was mainly present in spongiotrophoblast cells of the junctional zone, as well as in the fetal vessels of the chorionic plate, the umbilical cord and in maternal myometrial smooth muscle. We observed a strain-specific placental increase of JAM-B protein expression from mid- to late gestation in Balb/c-mated C57BL/6 females, which was absent in DBA/2J-mated Balb/c females. Due to the essential role of progesterone during gestation, we further assessed a possible modulation of JAM-B in mid-gestational placentae deficient in the progesterone receptor (Pgr(-/-)) and observed an increased expression of JAM-B in Pgr(-/-) placentae, compared to Pgr(+/+) tissue samples. We propose that JAM-B is an as yet underappreciated trophoblast lineage-specific protein, which is modulated via the progesterone receptor and shows unique strain-specific kinetics. Future work is needed to elucidate its possible contribution to placental processes necessary to ensuring its integrity, ultimately facilitating placental development and fetal growth.

The presence of maternal cells in the organs of the offspring is referred to as maternal microchimerism (MMc). MMc is physiologically acquired during pregnancy and lactation and can persist until adulthood. The detection of MMc in a variety of human diseases has raised interest in the short- and long-term functional consequences for the offspring. Owing to limited availability and access to human tissue, mouse models have become an essential tool in elucidating the functional role of MMc. This review compiles the detection techniques and experimental settings used in murine MMc research. It aims to summarize the potential mechanisms of migration of MMc, pre- and postnatal tissue distribution, phenotype and concatenated function, as well as factors modulating its occurrence. In this context, we propose MMc to be a materno-fetal messenger with the capacity to critically shape the development of the offspring's immunity.

Immunological identity is traditionally defined by genetically encoded antigens, with equal maternal and paternal contributions as a result of Mendelian inheritance. However, vertically transferred maternal cells also persist in individuals at very low levels throughout postnatal development. Reciprocally, mothers are seeded during pregnancy with genetically foreign fetal cells that persist long after parturition. Recent findings suggest that these microchimeric cells expressing non-inherited, familially relevant antigenic traits are not accidental 'souvenirs' of pregnancy, but are purposefully retained within mothers and their offspring to promote genetic fitness by improving the outcome of future pregnancies. In this Review, we discuss the immunological implications, benefits and potential consequences of individuals being constitutively chimeric with a biologically active 'microchiome' of genetically foreign cells.

The immune system is highly receptive to endocrine signals due to the expression of hormone receptors on immune cells. The impact of this immune–endocrine cross talk and related immune responses becomes clearly evident when assessing immunity from a sex-specific perspective. We here describe the effect of hormones, primarily sex- and stress-related steroid hormones, on cells of the innate and adaptive immune system in men and women. We specify how these effects are operational throughout the life span and also during periods of dramatic hormonal changes, such as pregnancy.

Maternal microchimerism, which occurs naturally during gestation in hemochorial placental mammals upon transplacental migration of maternal cells into the fetus, is suggested to significantly influence the fetal immune system. In our previous publication, we explored the sensitivity of quantitative polymerase chain reaction and flow cytometry to detect cellular microchimerism. With that purpose, we created mixed cells suspensions in vitro containing reciprocal frequencies of wild type cells and cells positive for enhanced green fluorescent protein or CD45.1(+), respectively. Here, we now introduce the H-2 complex, which defines the major histocompatibility complex in mice and is homologous to HLA in human, as an additional target to detect maternal microchimerism among fetal haploidentical cells. We envision that this advanced approach to detect maternal microchimeric cells by flow cytometry facilitates the pursuit of phenotypic, gene expression and functional analysis of microchimeric cells in future studies.

as in the 1st trimester trophoblast cell line HTR-8/SVneo. Isolated blood monocytes where cultured and differentiated in the presence of IL-34 for six days. When analyzed with flow cytometry, they showed high expression of CD14, CD163 (scavenger receptor), CD206 (mannose receptor) and CD209 (DC-SIGN), markers expressed on decidual macrophages. Taken together, our results show that IL-34 is produced both by placental and decidual cells and is able to induce macrophages with a phenotype resembling that of decidual macrophages. The findings suggest a role for IL-34 in the regulation of decidual macrophages during early pregnancy.

and IL10, as shown by neutralizing antibodies. PE CM also induced an increased proportion of CD25highFoxp3+ Tregs producing IL10. These Tregs were CD127low, expressed the suppressive markers CTLA-4 and CD39, and were predominantly CD45R0+, similar to the Tregs in early pregnancy decidual. In contrast, IFN(-producing Tbet+ cells (Th1), IL13-producing GATA3+ cells (Th2), and IL17-producing Ror(t+ cells (Th17) were not significantly induced upon PE CM stimulation. The expansion of CD25highFoxp3+ Tregs was also induced by CTB and EVT. Neutralization experiments showed that several factors including IL10, TGF(, and sTRAIL were responsible for the induction of Tregs. In addition, when CD4+ T cells activated by anti-CD3/CD28 antibodies were exposed to PE CM, the level of Th cell activation was significantly reduced, as shown by decreased HLA-DR expression and reduced cytokine secretion. HTR8 CM possessed some, but not all, of the above-mentioned properties, possibly because of their inability to produce IL10. Altogether, our data show that trophoblasts promote thepolarizationofhomeostaticmacrophages, contribute to the induction of Tregs, and limit excessive Th cell activation supporting the tolerant environment required for normal fetal development.