Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood

Lluis, Anna ; Depner, Martin ; Gaugler, Beatrice ; Saas, Philippe ; Casaca, Vera Isabel ; Raedler, Diana ; Michel, Sven ; Tost, Jorg

; Liu, Jing ; Genuneit, Jon

; Pfefferle, Petra ; Roponen, Marjut

; Weber, Juliane ; Braun-Fahrländer, Charlotte ; Riedler, Josef ; Lauener, Roger

; Vuitton, Dominique Angèle ; Dalphin, Jean-Charles ; Pekkanen, Juha ; von Mutius, Erika

; Schaub, Bianca ; Hyvärinen, A. ; Karvonen, A. ; Hirvonen, M.R. ; Tiittanen, P. ; Remes, S. ; Kaulek, V. ; Dalphin, M.L. ; Ege M, M. ; Büchele, G. ; Bitter, S. ; Loss, G. ; Roduit, C. ; Frei, R. ; Renz, H. ; Kabesch, M. ; Doekes, G.

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Background: European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. Objective: We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. Methods: From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis. Results: Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. Conclusions: Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.

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