Modulation of dendritic cell differentiation and function by human milk oligosaccharides

Michiko Shimoda, School of Medicine, University of California, Davis, USA

Michiko Shimoda1, Ace Gita Galermo2, Laura Olney1, Daniela Barile3, Bruce German3, Carlito Lebrilla2, and Emanual Maverakis1
1. Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, CA;
2. Department of Chemistry, University of California, Davis;
3. Department of Food Science and Technology, University of California, Davis

Human milk oligosaccharides (HMO) are a family of structurally diverse (~200 species) unconjugated glycans that are highly abundant in (5-20 mg/mL), and unique to, human milk. In addition to multiple beneficial effects, there is evidence suggesting that HMO modulate immune cell responses by attenuating responses to surface inflammatory stimuli, while enhancing signals that support maturation of the intestinal mucosal immune system. However, how various types of glycans interact with immune cells through receptors and modulate their differentiation and functions is not fully understood.

Dendritic cells (DC) are professional antigen presenting cells that are essential in orchestrating innate and adaptive immune responses in various stages of health and diseases. Previous studies have shown that manipulating DC functions is an effective approach to direct or re-direct the immune response for favorable outcomes. Furthermore, identifying safe and effective ways to modify DC functions could have tremendous benefits in human health. In this project, we tested the hypothesis that HMO modulate DC function and differentiation. We employed an established in vitro system to generate DC from monocytes or umbilical cord blood hematopoietic stem cells in the presence or absence of a group of HMO. We also studied the effect of HMO on acute DC response to danger- and pathogen- associated molecular patterns. The phenotypic and functional changes in DC were determined by flow cytometry, multiplex bioassay and gene expression analysis.

We found that DC differentiated from monocytes or hematopoietic stem cells in the presence of HMO showed substantial phenotypic and functional changes. For instance, monocyte-derived DC that developed in the presence of HMO, compared to those that developed in the absence of HMO, produced significantly reduced amounts of proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS) or double stranded RNA. Furthermore, after exposure to HMO, blood DC from healthy donors became much less responsive to acute stimulation with LPS or double stranded RNA. The latter was evident by significantly reduced production of Type-I interferons and pro-inflammatory cytokines in association with reduced expression of NFkB downstream target genes. Importantly, this ‘tolerance’ induction in DC was dependent on the presence of sialyl-glycans in HMO. Thus, these results support the hypothesis that HMO play a pivotal role in modulating the immune system by targeting DC differentiation and function.

Interestingly, many unconjugated glycans are also present in bovine milk, a component of which may carry a similar modulatory function in humans. Thus, based on our findings, a project is ongoing with our experimental system to further characterize bovine glycan components with immune modulatory functions, for disease prevention and therapies.

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