Changes in thymic regulatory T-cell maturation from birth to puberty: Differences in atopic children

Background: Characterization of regulatory immune pathways is a research priority for both the pathogenesis of allergic disease and potential therapeutic strategies. Objective: The thymus is a rich source of regulatory T (Treg) cells, which offers a novel opportunity to document the maturation of these pathways beyond limited studies on small volumes of peripheral blood available from young children. Methods: Thymus tissue was collected from children undergoing cardiac surgery (age, 1 week to 14 years), and skin prick testing was performed from 12 months of age. The ontogeny of Treg cell maturation and function was examined in atopic (n = 20) and nonatopic (n = 20) children by assessing their phenotype, enumeration, proliferation, and suppressive ability. Results: Age-related changes in the thymic cytokine milieu paralleled the changes seen in peripheral immune function. Specifically, the thymic microenvironment is similarly T-H(2) skewed during the early postnatal period, and this undergoes age-related suppression as the T-H(1) (IFN-gamma) response increased. We detected CD4(+)CD25(+)CD127(lo/-) forkhead box protein 3 (FOXP3)-positive Treg cells in the neonatal thymus. These cells suppressed the proliferative response to allogeneic stimulation of CD4(+)CD25(-) T cells dose dependently. In nonatopic children Treg cell turnover and suppressive function increased with age and paralleled the increase in global thymic FOXP3 mRNA expression, whereas in atopic children Treg cell maturation was significantly delayed compared with that seen in age-matched nonatopic children. Conclusion: These data suggest that the developmental changes in the thymus parallel the recognized changes in peripheral blood responses. There is also a developmental delay in the function of thymic regulatory cells in atopic compared with nonatopic children. These differences are fundamental to understanding early events that lead to immune dysregulation and might predispose to allergic disease. (J Allergy Clin Immunol 2012;129:199-206.)