Clinically, it's been well observed that children with disruptions to their microbiota during infancy (<1year old) have an increased risk for allergies. This has been widely reported and connected to the developing microbiota at this time. (A thread)
A good portion of the later half of my postdoc @newberrylab was focused on mechanisms regulating exposure of the immune system to the microbiota prior to weaning, which we applied to #allergies , and I'll summarize here.
We addressed the question by focusing on WHEN proteins are delivered to the dendritic cells in the intestine. We knew bacterial proteins were delivered to the colon during a very specific window: 10-21 days in a mouse, right before weaning. immunology.sciencemag.org/content/2/18/e…
We asked if dietary antigens, including the potential allergen OVA, or egg protein, were delivered in a similar time specific manner, and found A LOT happened during this two week window. insight.jci.org/articles/view/…
1) Dietary proteins were also delivered to the colon prior to weaning, directed there past the small intestine by proteins in breastmilk. Maternal EGF "shut off" the antigen delivery pathways in the intestine until the immune system was prepared to induce tolerance.
2) Temporal decreases in EGF then allow the colon to "open" first, showing the synchronization of mother and infant. Targeting protein delivery to this organ during this time results in long-living suppressive Tregs that express RORgt.
If we deleted the Tregs only developing during infancy from the system, the mice were prone to TH2 and allergic responses to OVA. frontiersin.org/articles/10.33…
If we disrupted breastfeeding, and initiated antigen delivery either too early or not at all, the mice were again prone to TH2 and allergic response to OVA. insight.jci.org/articles/view/…
Interestingly, when we exposed mice to OVA in their water, which should induce oral tolerance, AFTER either disrupting breastfeeding or removing the Tregs, the mice were still prone to allergic responses. insight.jci.org/articles/view/…
So the "Window of tolerance" that we talk about seems to be regulated by breastfeeding and for the purpose of educating Tregs in the colon to both dietary and bacterial antigens. These Tregs can suppress FUTURE inflammatory responses towards antigens they haven't yet encountered
This work has implications for formula feeding, antibiotic use during the first year of life, and understanding the connection between the microbiota and Treg development, which we review here: pubmed.ncbi.nlm.nih.gov/33403739/
This work couldn’t have been done without the help of @john_vini @KeelyGMcDonald @Hogan_Lab in the primary work, and @Lila_yokano with the review.
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