Microbial and Maternal Factors Control the Development of RORγt+ Regulatory T Cells Promoting Durable Tolerance and Preventing Allergy

Abstract

Abstract Mounting evidence emphasizes the importance of exposure to food allergens and gut microbes in early life to promote tolerance and reduce the risk of food allergy. Indeed the NIAID recently recommended early introduction of dietary peanut to reduce peanut allergy in at risk children. The mechanisms promoting tolerance during early life are incompletely understood, but potentially relate to a population of long-lived RORγt+ inducible regulatory T cells (iTregs) which prevent the development of food-specific Th2 responses throughout life. The optimal time for exposure to environmental antigens for the development of these RORγt+ iTregs, where in the gut protective exposures occur, and how the immune system’s contact with these antigens is controlled in early life remain unknown. We identified a window of time in early life in which luminal antigens are shunted to the colonic lamina propria (LP) and delivered to colonic LP antigen presenting cells by goblet cell-associated antigen passages (GAPs), correlating to an expansion of colonic LP RORγt+ iTregs. GAP formation was regulated by goblet cell sensing of breast milk epidermal growth factor and the blooming gut microbiota. Disruption of the gut microbiota or GAP formation and antigen delivery during early life abrogated tolerance to dietary antigens, decreased RORγt+ iTregs, and induced a skewing of the immune system toward systemic Th2 (allergic) responses. We propose the gut microbiota, in concert with maternal factors, control antigen delivery and the induction of RORγt+ iTregs during infancy. These mechanisms allow for proper education of the immune system against reaction to dietary and microbial antigens, a process that then suppresses inappropriate Th2 responses later in life.