title: Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation.
abstract: BACKGROUND
  Breastfeeding has protective effects for the development of allergies and atopy. Recent evidence underlines that consumption of unboiled farm milk in early life is a key factor preventing the development of atopic diseases. Farm milk intake has been associated with increased demethylation of FOXP3 and increased numbers of regulatory T cells (Tregs). Thus, the questions arose which components of farm milk control the differentiation and function of Tregs, critical T cell subsets that promote tolerance induction and inhibit the development of allergy and autoimmunity.
  
  
  RESULTS
  Based on translational research we identified at least six major signalling pathways that could explain milk's biological role controlling stable FoxP3 expression and Treg differentiation: (1) via maintaining appropriate magnitudes of Akt-mTORC1 signalling, (2) via transfer of milk fat-derived long-chain ω-3 fatty acids, (3) via transfer of milk-derived exosomal microRNAs that apparently decrease FOXP3 promoter methylation, (4) via transfer of exosomal transforming growth factor-β, which induces SMAD2/SMAD3-dependent FoxP3 expression, (5) via milk-derived Bifidobacterium and Lactobacillus species that induce interleukin-10 (IL-10)-mediated differentiation of Tregs, and (6) via milk-derived oligosaccharides that serve as selected nutrients for the growth of bifidobacteria in the intestine of the new born infant.
  
  
  CONCLUSIONS
  Accumulating evidence underlines that milk is a complex signalling and epigenetic imprinting network that promotes stable FoxP3 expression and long-lasting Treg differentiation, crucial postnatal events preventing atopic and autoimmune diseases.
authors.affiliation: Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, 49090 Osnabrück, Germany.
authors.forename: Bodo C
authors.initials: BC
authors.lastname: Melnik
authors.affiliation: Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, 49090 Osnabrück, Germany.
authors.forename: Swen Malte
authors.initials: SM
authors.lastname: John
authors.affiliation: Center for Primary Health Care Research, Lund University, Lund, Sweden.
authors.forename: Pedro
authors.initials: P
authors.lastname: Carrera-Bastos
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, University of Regensburg, Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
keywords: Epigenetic; Exosome; FoxO1; FoxP3; MicroRNA; Milk; Probiotics; TGF-β; Treg; mTORC1