Gene-regulatory programs that specify age-related differences during thymocyte development.

T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene-regulatory programs and their link to age-related differences. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern the effector response and cell cycle.

In utero per - and polyfluoroalkyl substances (PFAS) exposure and changes in infant T helper cell development among UPSIDE-ECHO cohort participants.

Background: Environmental exposures to toxicants, such as per- and polyfluoroalkyl substances (PFAS), during gestation can disrupt immune development, causing long-term impacts on a child's ability to generate a well-regulated, protective immune response. T-cells coordinate with all immune cell types to orchestrate both cellular and antibody-mediated responses. While there is compelling evidence that PFAS alters immunity in humans, the specific effects of early life PFAS exposure on infant T-cell development are unreported.

Maternal vaginal and fecal microbiota in later pregnancy contribute to child fecal microbiota development in the ECHO cohort.

There is growing interest in the use of microbial-seeding interventions to mitigate the impacts of prenatal antibiotics, C-section, and lack of breastfeeding on mother-child microbe sharing. However, the relative importance of maternal vaginal vs. fecal microbiota in this process is unclear.

Feeding Expressed Breast Milk Alters the Microbial Network of Breast Milk and Increases Breast Milk Microbiome Diversity over Time.

Breastfeeding supplies nutrition, immunity, and hormonal cues to infants. Feeding expressed breast milk may result in de-phased milk production and feeding times, which distort the real-time circadian cues carried by breast milk. We hypothesized that providing expressed breast milk alters the microbiotas of both breast milk and the infant's gut.

In utero exposure to per - and polyfluoroalkyl substances (PFAS) associates with altered human infant T helper cell development.

Background: Environmental exposures to chemical toxicants during gestation and infancy can dysregulate multiple developmental processes, causing lifelong effects. There is compelling evidence of PFAS-associated immunotoxicity in adults and children. However, the effect of developmental PFAS exposure on infant T-cell immunity is unreported, and, if present, could be implicated in immune-related health outcomes.

Affective symptoms in pregnancy are associated with the vaginal microbiome.

Background: Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Therefore, identifying sources of individual differences in the vaginal microbiome is of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure.

Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development.

T cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation.

Affective Symptoms in Pregnancy are Associated with the Vaginal Microbiome.

Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Identifying the sources of individual differences in the vaginal microbiome is therefore of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure.

Prenatal maternal immune activation predicts observed fearfulness in infancy.

Fear reactivity is an early emerging temperament trait that predicts longer term behavioral and health outcomes. The current analysis tests the hypothesis, an extension of prior research on maternal immune activation (MIA), that the prenatal maternal immune system is a reliable predictor of observed fear reactivity in infancy. The analysis is based on a prospective longitudinal cohort study that collected data from the first trimester and conducted observational assessments of temperament at approximately 12 months of age ( = 281 infants).

The gene regulatory basis of bystander activation in CD8 T cells.

CD8 T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8 T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8 T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens.

Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice.

Background: Thrombocytopenia is common in preterm neonates. Platelet transfusions are sometimes given to thrombocytopenic neonates with the hope of reducing the bleeding risk, however, there are little clinical data to support this practice, and platelet transfusions may increase the bleeding risk or lead to adverse complications. Our group previously reported that fetal platelets expressed lower levels of immune-related mRNA compared with adult platelets.

Aberrant newborn T cell and microbiota developmental trajectories predict respiratory compromise during infancy.

Neonatal immune-microbiota co-development is poorly understood, yet age-appropriate recognition of - and response to - pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 preterm and 119 full-term infants from birth through one year of age, we found that postmenstrual age or weeks from conception is a central factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained; however, by either age metric and are instead shaped by discrete perinatal and postnatal events.

MicroRNA-29 specifies age-related differences in the CD8+ T cell immune response.

MicroRNAs (miRNAs) have emerged as critical regulators of cell fate in the CD8+ T cell response to infection. Although there are several examples of miRNAs acting on effector CD8+ T cells after infection, it is unclear whether differential expression of one or more miRNAs in the naive state is consequential in altering their long-term trajectory. To answer this question, we examine the role of miR-29 in neonatal and adult CD8+ T cells, which express different amounts of miR-29 only prior to infection and adopt profoundly different fates after immune challenge.

Eight practices for data management to enable team data science.

Introduction: In clinical and translational research, data science is often and fortuitously integrated with data collection. This contrasts to the typical position of data scientists in other settings, where they are isolated from data collectors. Because of this, effective use of data science techniques to resolve translational questions requires innovation in the organization and management of these data.

Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development.

Background: Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factor , which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood.

Measuring the Severity of Respiratory Illness in the First 2 Years of Life in Preterm and Term Infants.

Objective: To develop a valid research tool to measure infant respiratory illness severity using parent-reported symptoms.

Study Design: Nose and throat swabs were collected monthly for 1 year and during respiratory illnesses for 2 years in a prospective study of term and preterm infants in the Prematurity, Respiratory Outcomes, Immune System and Microbiome study. Viral pathogens were detected using Taqman Array Cards.

Neonatal gut and respiratory microbiota: coordinated development through time and space.

Background: Postnatal development of early life microbiota influences immunity, metabolism, neurodevelopment, and infant health. Microbiome development occurs at multiple body sites, with distinct community compositions and functions. Associations between microbiota at multiple sites represent an unexplored influence on the infant microbiome.

T cell developmental arrest in former premature infants increases risk of respiratory morbidity later in infancy.

The inverse relationship between gestational age at birth and postviral respiratory morbidity suggests that infants born preterm (PT) may miss a critical developmental window of T cell maturation. Despite a continued increase in younger PT survivors with respiratory complications, we have limited understanding of normal human fetal T cell maturation, how ex utero development in premature infants may interrupt normal T cell development, and whether T cell development has an effect on infant outcomes. In our longitudinal cohort of 157 infants born between 23 and 42 weeks of gestation, we identified differences in T cells present at birth that were dependent on gestational age and differences in postnatal T cell development that predicted respiratory outcome at 1 year of age.

Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth.

Background: Identification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants.

Results: With weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively.

Immune and neuroendocrine correlates of temperament in infancy.

There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients.

Developmentally determined reduction in CD31 during gestation is associated with CD8+ T cell effector differentiation in preterm infants.

Homeostatic T cell proliferation is more robust during human fetal development. In order to understand the relative effect of normal fetal homeostasis and perinatal exposures on CD8+ T cell behavior in PT infants, we characterized umbilical cord blood CD8+ T cells from infants born between 23-42weeks gestation. Subjects were recruited as part of the NHLBI-sponsored Prematurity and Respiratory Outcomes Program.

Preterm cord blood CD4⁺ T cells exhibit increased IL-6 production in chorioamnionitis and decreased CD4⁺ T cells in bronchopulmonary dysplasia.

Background: Chorioamnionitis (CA) is associated with premature delivery and bronchopulmonary dysplasia (BPD). We hypothesize that preterm infants exposed to CA have reduced suppressive regulatory T cells (Treg) and increased non-regulatory T cell pro-inflammatory cytokines, increasing risk for BPD.

Objective: To evaluate cord blood CD4(+) T cell regulatory phenotype and pro-inflammatory cytokine production in CA and BPD groups.

Stability of T cell phenotype and functional assays following heparinized umbilical cord blood collection.

Umbilical cord blood has been used for a wide variety of immunologic investigations including assessments of developmental perturbations by antenatal exposures. Recent advances in multiparameter flow cytometry have allowed finer characterization of lymphocyte phenotype and function, revealing important differences between the fetal and adult immune systems. The degree of variability between human subjects confounds the ability to draw firm conclusions.