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Proper early life immune development creates a basis for a healthy and resilient immune system, which balances immune tolerance and activation. Deviations in neonatal immune maturation can have life-long effects, such as development of allergic diseases. Evidence suggests that human milk oligosaccharides (HMOS) possess immunomodulatory properties essential for neonatal immune maturation. To understand the immunomodulatory properties of enzymatic or bacterial produced HMOS, the effects of five HMOS (2'FL, 3FL, 3'SL, 6'SL and LNnT), present in human milk have been studied. A PBMC immune model, the IEC barrier model and IEC/PBMC transwell coculture models were used, representing critical steps in mucosal immune development. HMOS were applied to IEC cocultured with activated PBMC. In the presence of CpG, 2'FL and 3FL enhanced IFNγ ( < 0.01), IL10 ( < 0.0001) and galectin-9 ( < 0.001) secretion when added to IEC; 2'FL and 3FL decreased Th2 cell development while 3FL enhanced Treg polarization ( < 0.05). IEC were required for this 3FL mediated Treg polarization, which was not explained by epithelial-derived galectin-9, TGFβ nor retinoic acid secretion. The most pronounced immunomodulatory effects, linking to enhanced type 1 and regulatory mediator secretion, were observed for 2'FL and 3FL. Future studies are needed to further understand the complex interplay between HMO and early life mucosal immune development.