'Layered immunity' and the 'neonatal window of opportunity' - timed succession of non-redundant phases to establish mucosal host-microbial homeostasis after birth

Abstract

The intricate host-microbial interaction and the overwhelming complexity of the mucosal immune system in the adult host raise the question of how this system is initially established. Here, we propose the implementation of the concept of the 'postnatal window of opportunity' into the model of a 'layered immunity' to explain how the newborn's mucosal immune system matures and how host-microbial immune homeostasis is established after birth. We outline the concept of a timed succession of non-redundant phases during postnatal immune development and discuss the possible influence of external factors and conditions.

Keywords: layered immunity; mucosal immunology; neonatal window of opportunity; postnatal development.

Figure 1

Development of the mucosal immune system in the intestine under homeostatic conditions. At birth, the small intestine becomes readily colonized by a low‐diversity microbiota and microbial antigen and microbiota‐derived pathogen‐associated molecular patterns (PAMPs) become available. Simultaneously, endogenous innate immune stimuli are produced and a perinatal Toll‐like receptor (TLR) stimulation induces innate hyporesponsiveness and reprogramming in the intestinal epithelium and myeloid cells. Around birth, T and B cells exit from the thymus and bone marrow, respectively, and home to secondary lymphoid tissues (SLO) including the mesenteric lymph nodes and gut‐associated lymphoid tissues (e.g. Peyer's patches and solitary intestinal lymphoid tissues). Microbiota – initially transferred from the mother at birth – is likely to be largely bound to breast‐milk‐derived maternal secretory IgA that shields microbial antigen from the adaptive immune system. Maternal secretory IgA and neonatal thymus‐derived regulatory T (tTreg) cells contribute to the naive state of the adaptive immune system throughout the postnatal phase. At weaning, the host starts to ingest solid food containing complex carbohydrates. This leads to an increased richness of the intestinal microbiota. The innate unresponsiveness of the epithelium is reversed and physiological tissue development is largely complete so that crypts with antimicrobial‐producing Paneth cells are found and mucus production is up‐regulated in goblet cells shielding the microbiota from the now responsive epithelium. At the same time, goblet cells start to transport luminal antigen to the underlying dendritic cells (DCs) in the lamina propria. In the SLOs, DCs present antigen to naive T cells and a transient (adaptive) immune activation is induced – the weaning reaction – characterized by pro‐inflammatory cytokines – tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ). At the same time, retinoic acid receptor‐related orphan receptor γt‐positive Treg cells are induced that promote tolerance and tune the mucosal immune system for appropriate responsiveness to immune stimuli in later life, protecting the host from immune‐mediated diseases. After weaning, the microbiota composition stabilizes and is less sensitive to perturbations such as incoming pathogens or antibiotic treatment. Luminal antigen is facilitated to the antigen‐presenting cells in a highly controlled manner and the homeostatic immune response is dominated by tolerance promoting Treg cells that in turn induce the production of endogenous IgA by plasma cells.

Figure 2

Approximate time kinetic and tentative functional interrelationship and directionality of the individual processes that govern the transition from the fetal to the neonatal, weaning and post‐weaning periods. Aspects of the microbiota (in green), and innate (blue) and adaptive (orange) immune system are depicted.