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Schröder, P. C.; Illi, S.; Casaca, V. I.; Lluis, A.; Boeck, A.; Roduit, C.; Depner, M.; Frei, R.; Genuneit, J.; Pfefferle, P. I.; Roponen, M.; Weber, J.; Braun-Fahrländer, C.; Riedler, J.; Dalphin, J. C.; Pekkanen, J.; Lauener, R.; Mutius, Erika von; Schaub, B. (2017): A switch in regulatory T cells through farm exposure during immune maturation in childhood. In: Allergy, Vol. 72, No. 4: pp. 604-615
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Abstract

BackgroundFarm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the asthma-protective' farm effect via Tregs during childhood immune maturation. MethodsTregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4(+)CD25(high)FOXP3(upper20%)). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. ResultsTreg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001;P(PI) = 0.051;P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN- (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). ConclusionsTregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.