Toll-like receptor 2 impacts the development of oral tolerance in mouse pups via a milk-dependent mechanism

Background: The role of breast-feeding in the development of oral tolerance and allergic diseases is controversial, which could be related to variability in milk components. Toll-like receptor 2 (TLR2) is an innate immune receptor implicated in regulating allergic disease development. Objectives: We examined whether deficiency of maternal TLR2 affects the normal development of oral tolerance and related immune parameters during lactation in a mouse model. Methods: Heterozygous TLR2^+/– pups from wild-type (WT) or TLR2^–/– dams were fed either by their biologic dam or a dam of the alternate genotype. Development of oral tolerance to ovalbumin, levels of tolerogenic CD103⁺ dendritic cells, and regulatory T (Treg) cells, as well as intestinal permeability, were evaluated in these pups. The levels of key immune mediators in milk from TLR2^–/– and WT mothers were also examined. Results: Heterozygous TLR2^+/– pups that were born to and nursed by TLR2^–/– dams exhibited impaired oral tolerance. This was prevented by cross-fostering onto WT (TLR2^+/+) dams. Impairments included selective elevation in anti-ovalbumin IgE in plasma following immunization, reduced numbers of tolerogenic dendritic cells and Treg cells in the intestinal tract, and increased intestinal permeability. TLR2 deficiency also affected milk content of insulin-like growth factor-1, IFN-γ, IL-6, and IL-13. Conclusion: Our results underline a critical role for TLR2 in regulating milk components that are essential for development of oral tolerance in early life and demonstrate the importance of considering the immune status of nursing mothers in studies of immune development and responses.