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Review
. 2016 May 12:6:18.
doi: 10.1186/s13601-016-0108-9. eCollection 2016.

Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation

Bodo C Melnik  1 , Swen Malte John  1 , Pedro Carrera-Bastos  2 , Gerd Schmitz  3
Affiliations
Review

Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation

Bodo C Melnik et al. Clin Transl Allergy. .

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.

Findings: 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.

Conclusion: 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.

Keywords: Epigenetic; Exosome; FoxO1; FoxP3; MicroRNA; Milk; Probiotics; TGF-β; Treg; mTORC1.

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Figures

Fig. 1
Fig. 1
Synoptic working model for milk-induced FoxP3 expression and regulatory T cell (Treg) differentiation. The transcription factors FoxO1, FoxO3a, SMAD3 and STAT3 all enhance FoxP3 expression. Milk exosomal microRNAs and TGFβ attenuate DNA methyltransferase (DNMT) expression promoting TSDR demethylation (AAs: amino acids; ω3-FAs; ω-3 fatty acids; HMO: human milk oligosaccacharides; I: insulin; IGF1: insulin-like growth factor-1; miRs: microRNA-148a, microRNA-29, microRNA-21; mTORC1: mechanistic target of rapamycin complex 1; TGFβ: transforming growth factor-β; STAT3: signal transducer and activator of transcription 3; TSDR: Treg-specific demethylated region)
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