BackgroundThe role of FOXP3+ regulatory T cells in the prevention against sensitization and allergy development is controversial.ObjectiveWe followed 65 newborn Swedish children from farming and non-farming families from birth to 3 years of age and investigated the relation between CD4+ T cell subsets in blood samples and development of sensitization and allergic disease.MethodsThe proportions of FOXP3+CD25high, CTLA-4+CD25+, CD45RO+, HLA-DR+, CCR4+ or α4β7+ within the CD4+ T cell population were examined by flow cytometry of blood samples at several time-points. Mononuclear cells were isolated from blood and stimulated with birch allergen, ovalbumin or the mitogen PHA, and the levels of IL-1β, IL-6, TNF, IFN-γ, IL-5 and IL-13 were measured. A clinical evaluation regarding the presence of allergen-specific IgE and allergy was performed at 18 and 36 months of age.ResultsMultivariate discriminant analysis revealed that children who were sensitized at 18 or 36 months of age had higher proportions of FOXP3+CD25high T cells at birth and at 3 days of life than children who remained non-sensitized, whereas allergy was unrelated to the neonatal proportions of these cells. The proportions of CTLA-4+CD25+ T cells were unrelated to both sensitization and allergy. The association between higher proportions of FOXP3+CD25high T cells and sensitization persisted after exclusion of farmer's children. Finally, a farming environment was associated with lower proportions of FOXP3+CD25high T cells in early infancy and to a more prominent T cell memory conversion and cytokine production.Conclusion & Clinical RelevanceOur results indicate that high proportions of FOXP3+CD25high T cells in neonates are not protective against later sensitization or development of allergy.
Highlights d FoxP3-specific ablation of Blimp1 results in expansion of dysfunctional T FR cells d Inducible deletion of Blimp1 in T FR cells impairs T FR stability and function d Blimp1 controls CTLA4 expression, IL-23R-CD25 and CXCR5-CCR7 axes in T FR cells d Blimp1 controls appropriate homing and positioning of T FR cells into the GC
Summary Both major subcategories of inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease are characterized by infiltration of the gut wall by inflammatory effector cells and elevated biomarkers of inflammation in blood and feces. We investigated the phenotypes of circulating lymphocytes in the two types of IBD in treatment‐naive pediatric patients by analysis of blood samples by flow cytometry. Multivariate analysis was used to compare the phenotypes of the blood lymphocytes of children with ulcerative colitis (n = 17) or Crohn’s disease (n = 8) and non‐IBD control children with gastrointestinal symptoms, but no signs of gut inflammation (n = 23). The two IBD subcategories could be distinguished based on the results from the flow cytometry panel. Ulcerative colitis was characterized by activated T cells, primarily in the CD8+ population, as judged by increased expression of human leukocyte antigen D‐related (HLA‐DR) and the β1‐integrins [very late antigen (VLA)] and a reduced proportion of naive (CD62L+) T cells, compared with the non‐IBD controls. This T cell activation correlated positively with fecal and blood biomarkers of inflammation. In contrast, the patients with Crohn’s disease were characterized by a reduced proportion of B cells of the memory CD27+ phenotype compared to the non‐IBD controls. Both the patients with ulcerative colitis and those with Crohn’s disease showed increased percentages of CD23+ B cells, which we demonstrate here as being naive B cells. The results support the notion that the two major forms of IBD may partially have different pathogenic mechanisms.
FOXP3+ and CTLA-4+ Tregs may modulate CD4+ T-cell activation and homing receptor expression in children.
The gut microbiota provides an important stimulus for the induction of regulatory T (Treg) cells in mice, whether this applies to newborn children is unknown. In Swedish children, Staphylococcus aureus has become a common early colonizer of the gut. Here, we sought to study the effects of bacterial stimulation on neonatal CD4+ T cells for the induction of CD25+ CD127low Treg cells in vitro. The proportion of circulating CD25+ CD127low Treg cells and their expression of FOXP3, Helios and CTLA-4 was examined in newborns and adults. To evaluate if commensal gut bacteria could induce Treg cells, CellTrace violet-stained non-Treg cells from cord or peripheral blood from adults were co-cultured with autologous CD25+ CD127low Treg cells and remaining mononuclear cells and stimulated with S. aureus. Newborns had a significantly lower proportion of CD25+ CD127low Treg cells than adults, but these cells were Helios+ and CTLA-4+ to a higher extent than in adults. FOXP3+ CD25+ CD127low T cells were induced mainly in neonatal CellTrace-stained non-Treg cells after stimulation with S. aureus. In cell cultures from adults, S. aureus induced CD25+ CD127low T cells only if sorted naive CD45RA+ non-Treg cells were used, but these cells expressed less FOXP3 than those induced from newborns. Sorted neonatal CD25+ CD127low T cells from S. aureus-stimulated cultures were still suppressive. Finally, blocking PD-L1 during stimulation reduced the induction of FOXP3+ CD25+ CD127low T cells. These results suggest that newborns have a higher proportion of circulating thymically derived Helios+ Treg cells than adults and that S. aureus possess an ability to convert neonatal conventional CD4+ T cells into FOXP3+ CD25+ CD127low Treg cells via the PD-1/PD-L1 axis.
IntroductionPrenatal and neonatal environmental factors, such as nutrition, microbes and toxicants, may affect health throughout life. Many diseases, such as allergy and impaired child development, may be programmed already in utero or during early infancy. Birth cohorts are important tools to study associations between early life exposure and disease risk. Here, we describe the study protocol of the prospective birth cohort, ‘Nutritional impact on Immunological maturation during Childhood in relation to the Environment’ (NICE). The primary aim of the NICE cohort is to clarify the effect of key environmental exposures—diet, microbes and environmental toxicants—during pregnancy and early childhood, on the maturation of the infant’s immune system, including initiation of sensitisation and allergy as well as some secondary outcomes: infant growth, obesity, neurological development and oral health.Methods and analysisThe NICE cohort will recruit about 650 families during mid-pregnancy. The principal inclusion criterion will be planned birth at the Sunderby Hospital in the north of Sweden, during 2015–2018. Questionnaires data and biological samples will be collected at 10 time-points, from pregnancy until the children reach 4 years of age. Samples will be collected primarily from mothers and children, and from fathers. Biological samples include blood, urine, placenta, breast milk, meconium, faeces, saliva and hair. Information regarding allergic heredity, diet, socioeconomic status, lifestyle including smoking, siblings, pet ownership, etc will be collected using questionnaires. Sensitisation to common allergens will be assessed by skin prick testing and allergic disease will be diagnosed by a paediatrician at 1 and 4 years of age. At 4 years of age, the children will also be examined regarding growth, neurobehavioural and neurophysiological status and oral health.Ethics and disseminationThe NICE cohort has been approved by the Regional Ethical Review Board in Umeå, Sweden (2013/18-31M). Results will be disseminated through peer-reviewed journals and communicated on scientific conferences.
Neurological examination of preterm babies at term may be unreliable in the prediction of neurological outcome at 12 months corrected age. For early prediction of neurological outcome cranial ultrasound examination was found to be more reliable.
Lineage commitment and differentiation into CD4 T cell subsets reflect an interplay between chromatin regulators and transcription factors (TF). Follicular T cell development is regulated by the Bcl6 TF, which helps determine the phenotype and follicular localization of both CD4 follicular helper T cells (T) and follicular regulatory T cells (T). Here we show that Bcl6-dependent control of follicular T cells is mediated by a complex formed between Bcl6 and the Mi-2β-nucleosome-remodeling deacetylase complex (Mi-2β-NuRD). Formation of this complex reflects the contribution of the intracellular isoform of osteopontin (OPN-i), which acts as a scaffold to stabilize binding between Bcl6 and the NuRD complex that together regulate the genetic program of both T and T cells. Defective assembly of the Bcl6-NuRD complex distorts follicular T cell differentiation, resulting in impaired T development and skewing of the T lineage toward a T1-like program that includes expression of Blimp1, Tbet, granzyme B, and IFNγ. These findings define a core Bcl6-directed transcriptional complex that enables CD4 follicular T cells to regulate the germinal center response.
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