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A switch in regulatory T cells through farm exposure during immune maturation in childhood
Author(s) -
Schröder P. C.,
Illi S.,
Casaca V. I.,
Lluis A.,
Böck A.,
Roduit C.,
Depner M.,
Frei R.,
Genuneit J.,
Pfefferle P. I.,
Roponen M.,
Weber J.,
BraunFahrländer C.,
Riedler J.,
Dalphin J.C.,
Pekkanen J.,
Lauener R.,
Mutius E.,
Schaub B.
Publication year - 2017
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.13069
Subject(s) - foxp3 , immunology , medicine , immune system , ionomycin , peripheral blood mononuclear cell , regulatory t cell , ex vivo , allergy , cd8 , splenocyte , lipopolysaccharide , andrology , il 2 receptor , endocrinology , in vivo , t cell , biology , stimulation , in vitro , microbiology and biotechnology , biochemistry
Background Farm 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. Methods Tregs 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 ( CD 4 + CD 25 high FOXP 3 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. Results Treg percentage before and after stimulation and FOXP 3 mRNA expression ex vivo decreased from age 4.5 to 6 years ( P (U, LPS ) < 0.001; P ( PI ) = 0.051; P ( FOXP 3 ) < 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 ‐γ ( 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). Conclusions Tregs 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.