Neonatal T Cells: A Reinterpretation.

We previously found that neonatal and adult CD8+ T cells adopt different fates after infection with specific pathogens because they are derived from a distinct progenitor cell that is distinguished by expression of Lin28b. In this report, we investigated if CD8+ T cells respond differently to unrelated pathogens in early life. To start, we compared gene expression profiles of neonatal and adult CD8+ T cells after stimulation with innate cytokines (IL-12 + IL-18). Interestingly, we found that neonatal CD8+ T cells are more responsive and express a distinct cytokine profile compared to their adult counterparts. To examine the biological significance of these age-related differences, we next adoptively transferred monoclonal populations of neonatal or adult CD8+ T cells into T cell-deficient recipients and compared their ability to mediate immune protection against an irrelevant strain of Listeria monocytogenes. Surprisingly, we found that neonatal donor cell displayed increased proliferation and effector functions, and the pathogen burden was significantly reduced when compared to recipients containing adult donor cells. We also found that Lin28b may be responsible for the enhanced responsiveness to innate cytokines in early life, as ectopic expression of Lin28b in adult cells enabled them to initiate a program of bystander activation that was analogous to neonates. Collectively, these findings indicate that neonatal CD8+ T cells possess innate-like functions during infections at the cost of generating memory, and these unique behaviors may be driven by high levels of Lin28b. We currently are employing ATAC-seq to determine whether Lin28b changes the program of bystander activation by altering the chromatin landscape.

Immunological memory, which protects organisms from re-infection, is a hallmark of the mammalian adaptive immune system and the underlying principle of vaccination. In early life, however, mice and other mammals are deficient at generating memory CD8+ T cells, which protect organisms from intracellular pathogens. The molecular basis that differentiates adult and neonatal CD8+ T cells is unknown. MicroRNAs (miRNAs) are both developmentally regulated and required for normal adult CD8+ T cell functions. We used next-generation sequencing to identify mouse miRNAs that are differentially regulated in adult and neonatal CD8+ T cells, which may contribute to the impaired development of neonatal memory cells. The miRNA profiles of adult and neonatal cells were surprisingly similar during infection; however, we observed large differences prior to infection. In particular, miR-29 and miR-130 have significant differential expression between adult and neonatal cells before infection. Importantly, using RNA-Seq, we detected reciprocal changes in expression of messenger RNA targets for both miR-29 and miR-130. Moreover, targets that we validated include Eomes and Tbx21, key genes that regulate the formation of memory CD8+ T cells. Notably, age-dependent changes in miR-29 and miR-130 are conserved in human CD8+ T cells, further suggesting that these developmental differences are biologically relevant. Together, these results demonstrate that miR-29 and miR-130 are likely important regulators of memory CD8+ T cell formation and suggest that neonatal cells are committed to a short-lived effector cell fate prior to infection.

Understanding links between thermal performance and environmental variation is necessary to predict organismal responses to climate change, and remains an ongoing challenge for ectotherms with complex life cycles. Distinct life stages can differ in thermal sensitivity, experience different environmental conditions as development unfolds, and, because stages are by nature interdependent, environmental effects can carry over from one stage to affect performance at others. Thermal performance may therefore respond to carryover effects of prior thermal environments, yet detailed insights into the nature, strength, and direction of those responses are still lacking. Here, in an aquatic ectotherm whose early planktonic stages (gametes, embryos, and larvae) govern adult abundances and dynamics, we explore the effects of prior thermal environments at fertilization and embryogenesis on thermal performance curves at the end of planktonic development. We factorially manipulate temperatures at fertilization and embryogenesis, then, for each combination of prior temperatures, measure thermal performance curves for survival of planktonic development (end of the larval stage) throughout the performance range. By combining generalized linear mixed modeling with parametric bootstrapping, we formally estimate and compare curve descriptors (thermal optima, limits, and breadth) among prior environments, and reveal carryover effects of temperature at embryogenesis, but not fertilization, on thermal optima at completion of development. Specifically, thermal optima shifted to track temperature during embryogenesis, while thermal limits and breadth remained unchanged. Our results argue that key aspects of thermal performance are shaped by prior thermal environment in early life, warranting further investigation of the possible mechanisms underpinning that response, and closer consideration of thermal carryover effects when predicting organismal responses to climate change.

Isolation strategies of regulatory T cells for clinical trials: Phenotype, function, stability, and expansion capacity

The thymus of mice and chickens contains at least four discrete populations of lymphoid cells: Two distinct cortical populations of small lymphocytes (early and late population), a hydrocortisone resistant and presumably medullary population of small lymphocytes, and a population of medium sized lymphocytes (prolymphocytes) (see Table I and Figure 3). These four cell types were identified with preparative cell separation techniques (e.g. cell electrophoresis, BSA-density gradient centrifugation, and velocity sedimentation) in combination with size distribution analysis. The combination of these techniques provides two-dimensional distribution patterns ('fingerprints') with high power of resolution. At present the two cortical populations of small lymphocytes cannot be identified as distinct populations by any other method. The physical parameters also provide useful markers for the identification and comparison of cellular subpopulations in animals of different ages, different strains, and to a certain degree even of different species. It is believed that each of these subpopulations is in itself heterogeneous in respect to antigen specificity, and it is proposed to call lymphocytes with different antigen specificity but identical physical characteristics 'isotypic lymphocytes'. The medium and large thymocytes serve as progenitors of the small thymic lymphocytes, as shown by different investigators. Small and larger lymphocytes are thus believed to represent different stages on developmental pathways (vertical heterogeneity). The different populations of small thymocytes, on the other hand, are believed to represent different independent pathways (horizontal heterogeneity). There is clearly the possibility that functionally distinct sublines of peripheral T-cells are generated by separate developmental pathways in the thymus, and the functional properties of single thymic cell types (e.g. of the thymic suppressor cells) may accordingly correspond to the functional properties of their peripheral progeny.

All organisms respond to their environments, and early life environments may be especially impactful. Alternative splicing has been implicated as one mechanism that may underlie the response of organisms to their environments. However, most studies of this type examine immediate effects of an environmental perturbation on patterns of alternative splicing; little is known about the long-term consequences of early life environments. Here, we show the early life environment exerts a lasting influence on patterns of alternative splicing in the pea aphid (Acyrthosiphon pisum). This species is sensitive to conspecific density (crowding), with a transgenerational (mother-to-daughter) wing polyphenism cued by this environmental signal. We demonstrate that the maternal environment during embryonic development alters daughters’ alternative splicing profiles independently of morph identity, and that these effects persist into adulthood. By comparing the magnitude of maternal-environment effects to morph-specific differences, we reveal that the influence of early environmental conditions on splicing is unexpectedly large. These findings suggest that environmental history can leave a persistent molecular imprint beyond its role in morph determination. More broadly, this work highlights the need to disentangle environmental and morph-specific transcriptomic variation in studies of developmental polyphenism and connects to broader efforts, across biology and medicine, to understand how early life experiences shape long-term molecular and physiological outcomes.

Educational attainment is one of the strongest predictors of Alzheimer’s and Related Dementias (ADRD). Yet, much remains unknown as to how early life factors, particularly early life cognitive function, and early life environments, such as family environments, help explain why education so robustly protects against later life dementia. Is the influence of educational attainment not so much the additional schooling, but rather antecedent factors, like early life cognition and family environments that both build cognitive reserve and predict subsequent educational attainment? In short, is education merely a proxy for these antecedent influences? Consequently, we use the Wisconsin Longitudinal Study, which includes 80 years of prospectively collected data on a sample of 1 in every 3 high school graduates, and a selected sibling, from the class of 1957. Sibling models, and the inclusion of prospectively collected early life cognitive function and educational histories, allows us to explore the role of these early life conditions and the role they play in shaping the relationship between education and ADRD. We find a robust independent influence of education on ADRD risk, early life family environments had little impact on the relationship. Adolescent cognition, however, which we show is influenced by family environments, does partly explain why educational attainment influences later life ADRD risk, though both adolescent IQ and education independently influence the risk for and resilience against dementia.

There is limited research on how family-related events are associated with sustainable working life, which is defined as the absence of long-term periods of unemployment, sickness absence, or disability pension. We aimed to investigate whether family-related events, such as living with children, marriage, or divorce, are associated with sustainable working life. We also examined whether these associations could be explained by health behaviours including physical activity, smoking, and alcohol consumption, as well as by genetic factors and early life environment. Registry data and surveys on family-related events, sustainable working life, and health behaviours of 49,611 Swedish twins in 1993-2016 were used. Cox proportional hazards regressions were applied to estimate the associations between family-related events and sustainable working life, while conditional Cox models for twin pairs accounted for confounding genetic factors and early life environment. Further, the analyses were stratified by health behaviours. The results showed that a change from being single living without children to being married and living with children was associated with a sustainable working life. Moreover, individuals who experienced divorce and single individuals who changed their status of living with children were less likely to experience a sustainable working life. Genetic factors and early life environment played a role in some associations. Those with healthy behaviours were more likely to have sustainable working lives despite changes in family life, compared with those with unhealthy behaviours. Family formation (i.e. change from being single to getting married and having children) is associated with sustainable working life, whereas divorce seems to decrease the possibility of sustainable working life. Health behaviours, as well as genetic factors and early life environment, also need to be considered with changes in family life to support sustainable working life.

The nutritional environment in early life is a key factor for brain development and function. It is important to understand the relationship between early life nutrition and academic achievement in adolescence. The Pacific Islands families (PIF) birth cohort(1) were born in the year 2000. When their child was 6 weeks old mothers were asked questions concerning food security over the last year. Two binary measures of food security were derived as previously used in PIF and also by the Ministry of Health (MOH). Records of academic achievement for 649 youth were obtained from the National Certificate of Educational Achievement database in 2019. Highest qualifications and a composite ranking score allowed achievement to be assessed at levels 1, 2 and 3 of NCEA and for University Entrance (UE, lowest to highest). More females (27%) than males (18%) achieved UE as their highest qualification and more males (40%) than females (31%) achieved level 1 or 2 as their highest qualification. UE was achieved by 25% of those born into food secure households and 17% from food insecure households. Logistic regression demonstrated that being female increased the odds of achieving UE 1.8 fold and food security a further 1.6 fold. The prevalence of food insecurity was not different by sex but high at 29% and 42% using the PIF and MOH measure of food insecurity respectively. This work emphasises the importance of maternal and early life food security for subsequent academic achievement and the well-being of future generations.

Several cross-sectional studies during the past 10 years have observed an increased risk of allergic outcomes for children living in damp or mouldy environments. The objective of this study was to investigate whether reported mould or dampness exposure in early life is associated with the development of allergic disorders in children from eight European birth cohorts. We analysed data from 31 742 children from eight ongoing European birth cohorts. Exposure to mould and allergic health outcomes were assessed by parental questionnaires at different time points. Meta-analyses with fixed- and random-effect models were applied. The number of the studies included in each analysis varied based on the outcome data available for each cohort. Exposure to visible mould and/or dampness during first 2 years of life was associated with an increased risk of developing asthma: there was a significant association with early asthma symptoms in meta-analyses of four cohorts [0-2 years: adjusted odds ratios (aOR), 1.39 (95% CI, 1.05-1.84)] and with asthma later in childhood in six cohorts [6-8 years: aOR, 1.09 (95% CI, 0.90-1.32) and 3-10 years: aOR, 1.10 (95% CI, 0.90-1.34)]. A statistically significant association was observed in six cohorts with symptoms of allergic rhinitis at school age [6-8 years: aOR, 1.12 (1.02-1.23)] and at any time point between 3 and 10 years [aOR, 1.18 (1.09-1.28)]. These findings suggest that a mouldy home environment in early life is associated with an increased risk of asthma particularly in young children and allergic rhinitis symptoms in school-age children.

Nutritional environment in early life is a key factor for brain development and function. It is important to understand the relationship between nutrition in early life and academic achievement in adolescence. The birth cohort of the Pacific Islands Families (PIF) study was born in the year 2000. When their child was six weeks old, mothers were asked questions concerning food security over the past year. Two binary measures of food security were derived as previously used in PIF and also by the Ministry of Health (MOH). In 2020, records of academic achievement from the National Certificate of Educational Achievement (NCEA) for 649 (317 female, 332 male) cohort members showed progressive achievement at levels 1, 2, and 3 of NCEA and allowed University Entrance (UE) to be assessed. The prevalence of food insecurity was not different for sex but high at 29% and 42% using the PIF and MOH definitions of food insecurity, respectively. More females (27%) than males (18%) achieved UE as their highest qualification, and more males (40%) than females (31%) achieved NCEA levels 1 or 2 as their highest qualification. UE was achieved by 25% of those born into food-secure households and 17% from food-insecure households. Logistic regression demonstrated that the odds of achieving UE were 1.8-fold (95% CI 1.2, 2.6, p = 0.003) higher in females than males and, independently, 1.6-fold (95% CI 1.1, 2.5 p = 0.026) higher if the household was food secure. This work emphasises the importance of maternal and early-life food security for subsequent academic achievement and the well-being of future generations.

BackgroundEarly life exposures may modify risk of inflammatory bowel diseases (IBD; Crohn’s disease (CD), ulcerative colitis (UC)). However, the relationship between early life exposures and natural history of IBD has not been previously examined.MethodsThis single center study included patients with CD or UC recruited in a prospective IBD registry. Enrolled patients completed a detailed environmental questionnaire that assessed various early life environmental exposures. Our primary outcome was requirement for disease-related surgery in CD and UC. Logistic regression models defined independent effect of early life exposures, adjusting for potential confounders.ResultsOur study included 333 CD and 270 UC patients. Just over half were female with a median age at diagnosis of 25 years. One-third of the cohort had history of bowel surgery (31%) and nearly half had used at least one biologic agent (47%). Among those with CD, being breastfed was associated with reduced risk of CD-related surgery (34% vs. 55%), while childhood cigarette smoke exposure was associated with increased risk. On multivariate analysis, history of being breastfed (odds ratio (OR) 0.21, 95% confidence interval [CI] 0.09–0.46) and cigarette smoke exposure as a child (OR 2.17, 95% CI 1.10–4.29) remained independently associated with surgery. None of the early life variables influenced disease phenotype or outcome in UC.ConclusionA history of being breastfed was associated with a decreased risk while childhood cigarette smoke exposure was associated with an increased risk of surgery in patients with CD. Further investigation to examine biological mechanisms is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-014-0216-8) contains supplementary material, which is available to authorized users.

Knowledge of environments used during early life history and movement patterns of Bighead Carp (Hypophthalmichthys nobilis) and Silver Carp (H. molitrix), collectively termed bigheaded carps, in the Upper Mississippi River (UMR) would be valuable for informing control measures to limit further population expansion and impacts of these species. Lock and Dam 19 (LD19) is a high-head dam on the UMR that delineates downriver areas where bigheaded carps are well established from upriver pools where these species are less abundant and evidence of reproduction and recruitment are limited. Principal natal environments supporting recruitment of emerging bigheaded carp populations in the UMR are unknown. The objectives of this study were to (1) infer environments occupied during early-life stages by bigheaded carps collected in UMR Pools 19–21 during 2013–2014 using otolith microchemistry and stable isotope analyses, and (2) use early-life environment assignments and capture location to identify individuals that passed through LD19. Differences in multivariate water chemistry signatures (Sr:Ca, Ba:Ca and δ18O) among the UMR, its tributaries, and the Missouri and Middle Mississippi rivers enabled development of a classification model for inferring early-life environment of bigheaded carps. Multiple sources of recruits, including from tributaries, have contributed to upriver expansion of bigheaded carps in the UMR. Sustainable control of bigheaded carps upstream of LD19 will likely require efforts to control local recruitment and immigration from downriver. The frequency of bigheaded carps collected in Pool 19 that were downstream of LD19 during early life suggests that bigheaded carps upstream of LD19 still predominantly consisted of immigrants from downriver during 2013–2014. Otolith chemistry provides an approach for assessing the extent to which changes in abundance of bigheaded carps upstream of LD19 are associated with local recruitment or immigration from downriver.

David J.P. Barker was a physician, a biologist and one of the most influential epidemiologists of our time. His ‘foetal programming hypothesis’ (‘Barker hypothesis’) transformed our thinking about the causes of diabetes, cardiovascular disease and cancer. He challenged the idea that they are explained by bad genes and unhealthy adult lifestyles, and proposed that their roots lie in the early life environment: ‘The nourishment a baby receives from its mother, and its exposure to infection after birth, determine its susceptibility to chronic disease in later life’. By permanently ‘programming’ the body’s metabolism and growth, they determine the pathologies of old age. His initially controversial, but now widely accepted, ideas have stimulated an explosion of research worldwide into early development and later disease (‘developmental origins of health and disease’ or DOHaD). David thought that ‘the poorer health of people in lower socio-economic groups or living in impoverished places is linked to neglect of the welfare of mothers and babies’. He argued that to pull back the modern epidemics of chronic disease we should prioritize the health and nutrition of girls, pregnant women and infants. David built his career in Southampton where, with Donald Acheson and Martin Gardner, the MRC Environmental Epidemiology Unit was established. He became its director in 1984. His research into the aetiology of thyroid disease, Perthes’ disease, Paget’s disease, appendicitis and chronic neurological disease led him to evidence of nutritional and infective influences in early life. He suspected that such influences caused the rapid waxing and waning of disease, for example the mysterious disappearance of rheumatic heart disease and new epidemic of coronary heart disease. The Unit’s detailed mapping of mortality (Atlas of Mortality for Selected Diseases in England and Wales, 1968-1978) led to his observation that areas with more infant mortality in 1910 had more cardiovascular deaths in 1970. He and statistician Clive Osmond confirmed strong geographical correlations between neonatal mortality and death from coronary heart disease and stroke decades later. He concluded that poor foetal nutrition was causally linked to later disease, and devoted the next three decades to a tenacious pursuit of evidence to support this. Interestingly his PhD thesis, ‘Prenatal influences and subnormal intelligence’, findings of which were published in 1966, was a harbinger of his foetal programming work. Using old birth records, he showed that people of lower birth and infant weight had more cardiovascular disease and diabetes in middle age. The latter of these papers is reprinted in this issue as part of the celebration of the centenary of the UK Medical Research Council, together with a commentary by David on his reflections on the thrifty phenotype hypothesis 20 years on. With the Helsinki Birth Cohort Group, he related patterns of childhood growth to these diseases. With colleagues in India, he showed similar relationships in developing populations. With the Dutch Hunger Winter Group in Amsterdam, he showed that exposure of mothers to famine left a legacy of ill health in their children. He collaborated with physiologists in Adelaide, Auckland and Toronto who were studying foetal development in animals, harnessing strong evidence that early life undernutrition had permanent effects on all body systems. The connections he made between the worlds of physiology and epidemiology were the forerunners of the International DOHaD Societyand congresses. There were some aspects of modern epidemiology that David disliked. He disagreed that consistency of Published by Oxford University Press on behalf of the International Epidemiological Association

Early Life Development of Cardiac Hypertrophy in Rat Offspring from Pregnancies Complicated by Gestational Diabetes Mellitus