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Exosomes with Immune Modulatory Features Are Present in Human Breast Milk¹

Charlotte Admyre^2,*, Sara M. Johansson^*, Khaleda Rahman Qazi^*, Jan-Jonas Filén, Riitta Lahesmaa, Mikael Norman, Etienne P. A. Neve, Annika Scheynius^* and Susanne Gabrielsson^*

^* Department of Medicine, Clinical Allergy Research Unit, Karolinska Institutet and University Hospital, Stockholm, Sweden; Turku Centre for Biotechnology, Turku, Finland; Department Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet and University Hospital, Stockholm, Sweden; and Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden

Breast milk is a complex liquid with immune-competent cells and soluble proteins that provide immunity to the infant and affect the maturation of the infant’s immune system. Exosomes are nanovesicles (30–100 nm) with an endosome-derived limiting membrane secreted by a diverse range of cell types. Because exosomes carry immunorelevant structures, they are suggested to participate in directing the immune response. We hypothesized that human breast milk contain exosomes, which may be important for the development of the infant’s immune system. We isolated vesicles from the human colostrum and mature breast milk by ultracentrifugations and/or immuno-isolation on paramagnetic beads. We found that the vesicles displayed a typical exosome-like size and morphology as analyzed by electron microscopy. Furthermore, they floated at a density between 1.10 and 1.18 g/ml in a sucrose gradient, corresponding to the known density of exosomes. In addition, MHC classes I and II, CD63, CD81, and CD86 were detected on the vesicles by flow cytometry. Western blot and mass spectrometry further confirmed the presence of several exosome-associated molecules. Functional analysis revealed that the vesicle preparation inhibited anti-CD3-induced IL-2 and IFN- production from allogeneic and autologous PBMC. In addition, an increased number of Foxp3⁺CD4⁺CD25⁺ T regulatory cells were observed in PBMC incubated with milk vesicle preparations. We conclude that human breast milk contains exosomes with the capacity to influence immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Swedish Research Council Grants 15243-01, 7924-18A, and 71P-14158 and by the Centre for Allergy Research at the Karolinska Institute, the Hesselman Foundation, the Jeansson Foundation, the European Science Foundation, the Åke Wiberg Foundation, the Magnus Bergvall Foundation, the Swedish Cancer and Allergy Foundation, and the Swedish Asthma and Allergy Association’s Research Foundation.

² Address correspondence and reprint requests to Dr. Charlotte Admyre, Department of Medicine, Clinical Allergy Research Unit L2:04, Karolinska Institutet and University Hospital, Stockholm, Sweden. E-mail address: Charlotte.Admyre{at}ki.se

³ Abbreviations used in this paper: MFG, milk fat globule; ACN, acetonitrile; CBA, cytometric bead array; EM, electron microscopy; Hsc70, heat shock cognate protein 70; LC, liquid chromatography; MDDC, monocyte-derived dendritic cell; MS, mass spectrometry; MS/MS, tandem MS; MUC-1, mucin-1; SFC, spot-forming cell.

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