Table 1 Translational evidence for milk-microRNA-mediated thymic Treg maturation

Milk contains abundant miRs

From all body fluids human milk contains the highest amounts of RNAs and miRs

[78–82, 84–87, 92]

Milk contains miR-155, miR-146a, and miR-21

MiR-155, miR-146a and miR-21 are crucial miRs involved in Treg maturation and function

[79–81, 84, 85, 87]

The majority of milk’s miRs are transported in exosomes

Exosomes transfer genetic information for cell-cell communications over short and long distances

[81, 82, 84–87, 92]

MiR-155 is a component of colostrum and bovine whey and is found to be transported in exosomes

MiR-155 is an ancient highly conserved miR involved in immune regulation

[84, 85]

Milk exosomes are resistant against RNase-degradation and acidic conditions (pH1-2)

Milk exosomes may survive the acidic environment of the stomach. Boiling of milk destroys the biological activity of milk miRs

[80, 81, 86]

Mir-155, miR-146a and miR-21 are components of human blood plasma

Milk miR-containing exosomes may be transported in circulation and may reach the thymus

[94, 95]

Bovine colostrum and bovine milk and human breast milk exosomes containing miRs are taken up by cells and increase cytoplasmic miR levels

Milk-derived miRs may be taken up by exosome endocytosis in recipient cells. Physical destruction of exosomal lipid bilayer structure abolishes cellular miR uptake

[82, 85, 92]

Exosomal transfer is a known mechanism of communication between immune cells

Macrophages, B-cell, T cells and thymocytes communicate via exosome transfer

[70–73, 91]

Human breast milk exosomes when added to PBMCs induce FoxP3⁺ Tregs

Breast milk miR-155 may induce the expression of FoxP3⁺ by inhibiting SOCS1 signaling

[82]

Exosomes have been detected in the murine and human thymus

Milk-derived exosomes may augment Treg cell maturation in the thymus

[74, 91]

Murine thymic exosomes when added to thymus CD4⁺CD25^- T cells induce CD4⁺CD25⁺FoxP3⁺ Treg cells

Milk-derived exosomes may promote Treg cell formation of developing thymocytes within the human thymic medulla

[74, 91]

MiR-21 and miR-29b inhibit DNMT1 expression in T cells

Milk miR-21 and miR-29b may promote stable expression of demethylated FoxP3 and thus lineage commitment of thymic Treg cells

[105, 106]