Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria

Abstract

We have a mutually beneficial relationship with the trillions of microorganisms inhabiting our gastrointestinal tract. However, maintaining this relationship requires recognizing these organisms as affable and restraining inflammatory responses to these organisms when encountered in hostile settings. How and when the immune system develops tolerance to our gut microbial members is not well understood. Here we identify a specific pre-weaning interval in which gut microbial antigens are encountered by the immune system to induce antigen specific tolerance to gut bacteria. Intriguingly for some bacterial taxa, physiologic encounters with the immune system are restricted to this interval, despite abundance of these taxa in the gut lumen at later times outside this interval. Antigen specific tolerance to gut bacteria induced during this pre-weaning interval is stable and maintained even if these taxa are encountered later in life in an inflammatory setting. However, inhibiting microbial antigen encounter during this interval or extending these encounters beyond the normal interval, results in a failure to induce tolerance and robust antigen specific effector responses to gut bacteria upon reencounter in an inflammatory setting. Thus, we have identified a defined pre-weaning interval critical for developing tolerance to gut bacteria and maintaining the mutually beneficial relationship with our gut microbiota.

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…Cessation of breastfeeding was identified as a major driving factor highlighting the critical influence of breast‐milk constituents on early host–microbial homeostasis . Beside lactose, human milk oligosaccharides, lactoferrin and secretory IgA may exert direct antibacterial effects whereas epidermal growth factor has a major influence on intestinal epithelial gene expression and immune development . Notably, major differences are found between breastfed and formula‐fed babies .…”

“…Lung Treg cells that mediate tolerance do not express the transcription factor Helios and are presumably induced in the periphery . Whereas the neonatal host harbors thymus‐derived Treg cells in the secondary lymphoid tissues of the intestine, microbiota‐dependent peripherally generated Treg cells that express the transcription factor retinoic acid receptor‐related orphan receptor γ t only expand in the 4th week of life …”

“…This microbial stimulation may also cause the reported transient interleukin‐22‐ (IL‐22) and IL‐23‐induced signal transducer and activator of transcription 3 phosphorylation in innate lymphoid type 3 cells and epithelial cells . Notably, the time‐point of the intestinal tolerization process and Treg cell generation is critical and delayed exposure to microbiota has far reaching consequences for health and disease in later life with increased susceptibility to immune‐mediated diseases such as inflammatory bowel disease, cancer, and allergic sensitization …”

“…On the other hand, premature activation of the adaptive immune system in the intestine can also lead to enhanced disease susceptibility. It can be induced by removing maternal immunoglobulin from breast milk or enforcing a premature transport of antigen to lamina propria dendritic cells via GAPs . The consequences of premature activation are under‐studied.…”

“…Interestingly, homeostatic signaling via the IL‐33/ST2 ( IL1rl1 ) axis, which is usually associated with tissue damage, appears to balance and adjust the degree of T‐cell anergy in the neonatal host . Also, the induction of peripheral tolerance to self‐antigen may have to precede the tolerance to microbial and dietary antigens at mucosal sites . Alternatively, the establishment of tolerance to dietary and microbial antigens (that change almost completely around weaning) may have to be postponed until a stable dietary and microbial exposure is reached.…”