PMID- 30900752 OWN - NLM STAT- MEDLINE DCOM- 20200522 LR - 20200522 IS - 1521-4141 (Electronic) IS - 0014-2980 (Print) IS - 0014-2980 (Linking) VI - 49 IP - 7 DP - 2019 Jul TI - Human milk oligosaccharides promote immune tolerance via direct interactions with human dendritic cells. PG - 1001-1014 LID - 10.1002/eji.201847971 [doi] 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. CI - (c) 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. FAU - Xiao, Ling AU - Xiao L AUID- ORCID: 0000-0001-8447-8922 AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. FAU - van De Worp, Wouter Rph AU - van De Worp WR AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. AD - Department of Respiratory Medicine, NUTRIM, Maastricht University Medical Center, Maastricht, The Netherlands. FAU - Stassen, Roderick AU - Stassen R AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. FAU - van Maastrigt, Celine AU - van Maastrigt C AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. FAU - Kettelarij, Nienke AU - Kettelarij N AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. FAU - Stahl, Bernd AU - Stahl B AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. FAU - Blijenberg, Bernadet AU - Blijenberg B AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. FAU - Overbeek, Saskia A AU - Overbeek SA AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. FAU - Folkerts, Gert AU - Folkerts G AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. FAU - Garssen, Johan AU - Garssen J AUID- ORCID: 0000-0002-8678-9182 AD - Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. FAU - Van't Land, Belinda AU - Van't Land B AUID- ORCID: 0000-0001-8601-5032 AD - Departments of Immunology and of Human Milk Research & Analytical Science, Danone Nutricia Research, Utrecht, The Netherlands. AD - Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190404 PL - Germany TA - Eur J Immunol JT - European journal of immunology JID - 1273201 RN - 0 (Cell Adhesion Molecules) RN - 0 (Cytokines) RN - 0 (DC-specific ICAM-3 grabbing nonintegrin) RN - 0 (Lectins, C-Type) RN - 0 (Oligosaccharides) RN - 0 (Receptors, Cell Surface) RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Animals MH - Breast Feeding MH - Cell Adhesion Molecules/metabolism MH - Cell Differentiation MH - Cells, Cultured MH - Cytokines/metabolism MH - Dendritic Cells/*immunology MH - Endocrine System/immunology MH - Female MH - Humans MH - Immune Tolerance MH - Infant MH - Infant, Newborn MH - Lectins, C-Type/metabolism MH - Lymphocyte Activation MH - Milk, Human/*metabolism MH - Oligosaccharides/*metabolism MH - Receptors, Cell Surface/metabolism MH - T-Lymphocytes, Regulatory/*immunology MH - Toll-Like Receptor 4/metabolism PMC - PMC6619030 OTO - NOTNLM OT - DC-SIGN OT - IL-10 OT - TLR4 OT - human milk oligosaccharides OT - regulatory T cells (Treg) COIS- None of the authors have a competing financial interest in relation to the presented work; JG is head of the Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science at the Utrecht University, and partly employed by Nutricia Research. NK, BS, BB, SO, and BL are employed by Nutricia Research. BL, as indicated by the affiliations, is leading a strategic alliance between University Medical Centre Utrecht/Wilhelmina Children's Hospital and Nutricia Research. EDAT- 2019/03/23 06:00 MHDA- 2020/05/23 06:00 PMCR- 2019/07/10 CRDT- 2019/03/23 06:00 PHST- 2018/10/15 00:00 [received] PHST- 2019/02/19 00:00 [revised] PHST- 2019/03/19 00:00 [accepted] PHST- 2019/03/23 06:00 [pubmed] PHST- 2020/05/23 06:00 [medline] PHST- 2019/03/23 06:00 [entrez] PHST- 2019/07/10 00:00 [pmc-release] AID - EJI4476 [pii] AID - 10.1002/eji.201847971 [doi] PST - ppublish SO - Eur J Immunol. 2019 Jul;49(7):1001-1014. doi: 10.1002/eji.201847971. Epub 2019 Apr 4.