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.