Programmed and environmental determinants driving neonatal mucosal immune development

Abstract

The mucosal immune system of neonates goes through successive, non-redundant phases that support the developmental needs of the infant and ultimately establish immune homeostasis. These phases are informed by environmental cues, including dietary and microbial stimuli, but also evolutionary developmental programming that functions independently of external stimuli. The immune response to exogenous stimuli is tightly regulated during early life; thresholds are set within this neonatal "window of opportunity" that govern how the immune system will respond to diet, the microbiota, and pathogenic microorganisms in the future. Thus, changes in early-life exposure, such as breastfeeding or environmental and microbial stimuli, influence immunological and metabolic homeostasis and the risk of developing diseases such as asthma/allergy and obesity.

Figure 1:. Kinetics of the development of the intestinal mucosa immune system.

(A) Time course of immune cell (IEL, CD4 LPL, Rorγt+ Treg) development in the intestine. (B) Time course of Immunoglobulin A (IgA) levels, Microbiota development (density and diversity in SI and colon) and lymphoid tissue development in the intestine. LPL, lamina propria lymphocyte; SIgA, secretory IgA; IEL, intraepithelial lymphocyte; SILT, solitary isolated lymphoid follicles; RORgt, RAR-related orphan receptor gamma t; Treg, regulatory T cell^{,,,–,,–,,,,,,,–.}

Figure 2:. Immune cell architecture of the developing mouse small intestine.

Left panel: The small intestine is quickly colonized after birth by a low diversity/high abundance microbiota partially bound by breast milk-derived SIgA. Cells of the innate immune system are present at birth both in gut associated lymphoid tissue (GALT)/lymph node (LN) as well as in the lamina propria (LP). In contrast, B and T lymphocytes begin to populate inductive lymphoid tissues around birth. Luminal antigen uptake is reduced due to the absence of goblet cell associated passages (GAP) in the LP and mature microfold (M) cells overlaying GALT resulting in the presence of naïve T and B lymphocytes throughout the postnatal period. Middle panel: During the third week of life mice begin to ingest solid food and complex carbohydrates that lead to a diversification of the microbiota. After weaning, breast milk SIgA disappears from the intestinal lumen and antigen uptake is now facilitated to the LP and GALT via GAPs and M cells, respectively. This induces microbial stimulation of antigen presenting cells, transient expression of proinflammatory cytokines by T cells and the formation of germinal centers in the lymphoid tissues. Immune priming at weaning (the weaning reaction) is orchestrated to start adaptive immune activation but prevent an overt stimulation of the host immune system. Right Panel: Priming of adaptive immune cells at the LN/GALT leads to antigen-experienced immune cells at effector sites. Germinal centers increase in size and lead to the population of the GALT and intestinal LP with IgA-producing plasma cells. T helper 17 and T regulatory cells specific to antigens from the microbiota are induced in MLN and travel to the LP MLN, mesenteric lymph node; F, follicle; IFR, interfollicular region; GC, germinal center; SFB, segmented filamentous bacteria; GALT, gut associated lymphoid tissue; SILT, solitary isolated lymphoid follicles; LP, lamina propria; GAP, goblet cell associated passage; T_reg, regulatory T cell, T_eff, effector T cell; B_naive, naïve B cell; B_act, activated B cell