Maternal influence on offspring food allergy

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Project Summary Food allergy (FA) is a growing public health concern. The effects of maternal immune responses on the induction of regulatory T (Treg) cell-mediated food tolerance in offspring are poorly understood. We found that maternal “protective” sensitization with allergen [ovalbumin (OVA) or peanut] prevented FA responses in murine offspring in response to epicutaneous sensitization and oral challenge with the same allergen, as indicated by a decrease in the levels of food anaphylaxis, allergen-specific immunoglobulin (Ig) E, serum mouse mast cell proteinase 1, and intestinal mast cell expansion. Neonatal Fc receptor (FcRn)-dependent transfer of maternal IgG and allergen immune complexes (IgG-IC) via milk and IgG-IC presentation by neonatal CD11c+ cells induced allergen-specific Treg cells in offspring. Offspring of unsensitized mothers fostered by OVA-sensitized mothers or maternal IgG- IC supplementation induced neonatal tolerance. Consistently, human milk from non-atopic mothers contained IgG-IC and induced tolerance in humanized FcRn mice. These results indicate that maternal milk IgG-IC-FcRn axis establishes Treg cell-mediated neonatal food tolerance, which may extend to humans. As an extension of our prior study, the goals of this proposal are the previously underinvestigated mechanisms by which additional milk factor (microbiota) besides IgG-ICs in a specific preweaning interval during lactation critically regulate the induction of retinoic acid receptor related orphan receptor γt (Rorγt)+ Treg cell-mediated neonatal tolerance against FA. Selective deletion of Rorc, the gene encoding Rorγt, in Forkhead box protein 3 (Foxp3)+ Treg cells predisposes to FA in wild-type (WT) mice. Offspring of OVA-sensitized WT mothers show higher frequencies of OVA-specific Rorγt+ Treg cells as compared to controls. Il4raF709 mice, a murine model of FA, carry a gain-of- function mutation in the interleukin (IL)-4 receptor (IL-4R) α chain allele. Il4raF709 offspring of OVA-sensitized Il4raF709 mothers showed failure of tolerance towards FA as compared to controls in the presence of IgG-IC, associated with decreased frequencies of Rorγt+ Treg cells. Bacteriotherapy with Clostridiales or Bacteroidales species induced Rorγt+ Treg cells that suppressed FA in Il4raF709 mice, suggesting that Rorγt+ Treg cells mediate protection against FA and that pro-atopic genotype may hinder the optimal induction of neonatal tolerance through the reprogramming of Rorγt+ Treg cells . Offspring of OVA-sensitized germ-free mothers and offspring of OVA-mothers treated with antibiotics during the lactation period failed to show protection against FA, even in the presence of IgG-IC. Our pilot study identified the differences in milk bacterial taxa and human milk oligosaccharides between non-atopic and FA groups. These results imply that the maternal microbiota during the lactation period is necessary to successfully induce neonatal food tolerance. We hypothesize that newly developed allergen-specific Rorγt+ Treg cells in the neonatal gut suppress Th2 responses to food allergen, and that this process is compromised by high Th2 signaling. We also hypothesize that the maternal microbiota during the lactation period shape the neonatal gut microbiota that induce the Treg cell-mediated neonatal food tolerance.