TY - JOUR
T1 - Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells
AU - Xiao, Ling
AU - van De Worp, Wouter Rph
AU - Stassen, Roderick
AU - van Maastrigt, Celine
AU - Kettelarij, Nienke
AU - Stahl, Bernd
AU - Blijenberg, Bernadet
AU - Overbeek, Saskia A.
AU - Folkerts, Gert
AU - Garssen, Johan
AU - Land, Belinda Van't
N1 - Funding Information:
Acknowledgments: The authors would like to thank A. Kostadi-nova and V. Ayechu-Muruzabal for their technical assistance and useful discussions, and M. Mank for providing the structural analysis and information of human milk oligosaccharides mixture. Research grant funding was received from the China Scholarship Council for LX, award No.201406050044.
Publisher Copyright:
© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2019/7
Y1 - 2019/7
N2 - Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed-infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T-cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi-maturation of human monocytes-derived DCs (moDCs), and elevated levels of IL-10, IL-27 and IL-6 but not IL-12p70 and TNF-alpha. Consistently, HMOS-conditioned human moDCs promoted Treg generation from naive CD4(+) T cells. Interestingly, HMOS limited LPS-induced maturation of human moDCs, while maintained IL-10 and IL-27 secretion and reduced LPS-induced production of IL-12p70, IL-6 and TNF-alpha. Furthermore, HMOS+LPS-stimulated DCs induced a higher frequency of Tregs and increased IL-10 production, while a reduction in Tbet+Th1 frequency and IFN-gamma production was detected as compared to LPS-DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC-SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system.
AB - Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed-infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T-cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi-maturation of human monocytes-derived DCs (moDCs), and elevated levels of IL-10, IL-27 and IL-6 but not IL-12p70 and TNF-alpha. Consistently, HMOS-conditioned human moDCs promoted Treg generation from naive CD4(+) T cells. Interestingly, HMOS limited LPS-induced maturation of human moDCs, while maintained IL-10 and IL-27 secretion and reduced LPS-induced production of IL-12p70, IL-6 and TNF-alpha. Furthermore, HMOS+LPS-stimulated DCs induced a higher frequency of Tregs and increased IL-10 production, while a reduction in Tbet+Th1 frequency and IFN-gamma production was detected as compared to LPS-DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC-SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system.
KW - DC-SIGN
KW - human milk oligosaccharides
KW - IL-10
KW - regulatory T cells (Treg)
KW - TLR4
KW - BREAST-MILK
KW - T-CELLS
KW - ACTIVATION
KW - PHENOTYPE
KW - INNATE
U2 - 10.1002/eji.201847971
DO - 10.1002/eji.201847971
M3 - Article
C2 - 30900752
SN - 0014-2980
VL - 49
SP - 1001
EP - 1014
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 7
ER -