Activation of the Intestinal Immune System

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It has been shown that the presence of intestinal microbiota plays an important role in the development and activation of IIS even if many effects are still ignored. Its role may be of particular importance in the neonatal period and could determine many of the outcomes in later life.

As newborns, GF animals exhibit an underdeveloped IIS, which can be normalized by bacterial colonization of the intestine with the fecal microbiota from a CV animal or human, within 3 weeks. In GF mice, PPs are poorly developed, and germinal centers are absent. The absence of digestive microbiota only affects some subsets of thymus-dependent IEL, the single positive thymo-dependent CD4 + or CD8 + ab IEL, the other thymo-independent homodimeric aa CD8 + subpopulations of IEL (all the gS-IEL and part of the ab IEL) being always present in GF mice (35). Cellularity of the LP is greatly reduced in GF mice and it has been demonstrated that the intestinal microbiota is the major target of the IgA plasmocyte development.

IgA-Secreting Cells

As in the neonate, the intestinal IgA-secreting cell (IgA-SC) number is much reduced in adult GF mice. Three weeks after bacterial colonization of the intestine, GF mice have an IgA-SC number equivalent to that found in CV mice. In the young, the adult number of IgA-SC is reached at the age of 6 weeks in mice and between 1 and 2 years in babies (7). This important delay might be attributed to the immaturity of the IIS of the newborn and/or the suppressive effect of Abs present in the mother's milk. However, it might also be due to the stimulatory effect of the intestinal microbiota that has been established according to a sequential manner from birth to after weaning as described previously. To test the later hypothesis, several models of adult gnotobiotic mice were colonized by the entire digestive microbiota obtained from growing CV mice from one day after birth to 25 days of age (i.e., 6 days after weaning; 62). In these experimental adult models, the effect of maternal milk, and the possible immaturity of the neonate were excluded, and only the stimulatory effect of the digestive microbiota was tested. After 4 weeks, adult recipients were sacrificed, and the immunostimulatory effect of the digestive microbiota evaluated by the IgA-SC numbers present in intestinal villi by immunohistochemical observations. Digestive microbiota of mice 3 to 21 days old exerted only a partial stimulatory effect on the intestinal IgA-SC number in gnotobiotic recipients (Table 1). However, gnotobiotic recipients colonized with the digestive microbiota of 25-day-old mice had a similar IgA-SC number to that found in adult CV mice.

These results obviously show the important role played by the sequential establishment of the digestive microbiota in full development of the intestinal IgA-SC number and the pivotal role played by the bacterial diversification present after weaning in this process. Results have been confirmed by other studies (7). Moreover, taking into account the 3-week delay between the bacterial stimulus and the intestinal IgA-SC response, these results showed that the neonate is capable of developing a sIgA response at birth, the intensity of which depends on the stimulatory capacity of the intestinal bacteria present in the intestine. It is tempting to project such results onto infants where the full development of the intestinal IgA-SC number observed at 2 years of age is correlated to the stabilization of the intestinal microbiota.

Table 1 Effect of the Sequential Establishment of Intestinal Microbiota of Growing CV Mice on the Maturation of Intestinal IgA Plasma Cells Measured in Gnotobiotic Mice

Gnotobiotic mice harboring the digestive flora of:

IgA plasma cell number/villus

Adult conventional mice

41 + 1

Adult germ-free mice

4 + 0.5

Growing conventional mice 1-4 days old

15 + 2

Growing conventional mice 7-23 days old

23 + 1

Growing conventional mice 25 days old

43 + 1

Attempts have been made to elucidate the role played by individual bacterial strains present in the digestive microbiota of CV growing mice (63). Results showed that some Gram-negative bacteria such as E. coli or Bacteroides play an important adjuvant role on this immunological non-specific effect, probably due to the LPS present in the cell wall of these bacteria (7). These studies have shown the importance of the intestinal microbiota diversification on the complete development of IIS in young. They promote insight into the close correlation between dietary modification and intestinal microbiota diversification and consequently its effect on the infantile IIS. Excessively early or late dietary modification may have consequences on quality of the intestinal microbiota equilibrium and, consequently, may affect the development of the IIS.

Dendritic Cells

As described above, the intestine is populated by some characteristic subsets of DCs, which are believed to play a pivotal role in the orientation of the acquired immune responses towards tolerance. Is the intestinal microbiota the main factor that determines such characteristics? Currently, only few studies exist in this field.

From some studies, it appears that inflammatory stimuli are very important for maturation of DCs in GF mice as well as in neonates, and the intestinal microbiota could afford such stimuli. It has been demonstrated that the rapid and constitutive trafficking of DCs from the IIS to the MLNs can be increased by the presence of inflammatory stimuli, such as LPS (64). Other studies have shown that it is possible to increase the rate of postnatal development of the intestinal DC population in rats by intra-peritoneally administration of IFN-g (65). We can conclude that these inflammatory factors are physiologically important to maintain activation of DCs and the intestinal microbiota may have an important part in this process.

Another question concerns the specific functions of intestinal DCs. Are there specific distinct lineages of DCs attracted into the intestinal mucosa under the control of specific chemokines or adhesion molecules, or are precursor DCs modified after their arrival in the tissue? In his interesting review (31), Mowat explains that, given the plasticity of DCs in other tissues, it is reasonable to believe the latter hypothesis, and mucosal DCs are the cells that integrate the genetic and environmental factors to shape T-cell responses to local Ags in ways such that homeostasis is maintained. Intestinal epithelial cells, by the ability to constitutively produce TGF-b and by the regulatory factors controlling inflammatory cytokine secretion, could be the first level of regulatory control. Moreover, recent studies have shown that lamina propria stromal cells constitutively produce cyclo-oxygenase 2 (COX2)-dependent protaglandin E2 (PGE2) under the influence of the physiological levels of LPS that are absorbed from intestinal microbiota. These metabolites act as down-regulators of the immune response to dietary Ags (66). Moreover, DCs themselves might also express COX2 and produce PGE2 in response to LPS. As PGE2 is known to polarize DC differentiation towards an IL-10-producing inhibitory phenotype, this would explain the prevalence of such DCs in the normal gut (67).

The subunit p40 is present in IL-12 and IL-23, which are both Th1-inducing cytokines. In a elegant study, Becker and coworkers (40) using transgenic mice expressing a reporter under the control of the IL-12p40 subunit promoter, showed that some subsets of lamina propria DCs, present in the small intestine but not in the colon, constitutively exhibited transgene expression. This expression was restricted to the ileum, associated with the intracellular nondegraded bacteria as revealed by fluorescent in situ hybridization (FISH), and was not found in the ileum of GF mice. In addition to supporting literature elsewhere (68), these results obviously show how the presence of the intestinal microbiota, which become more abundant in the ileum, can influence the immune responses elicited at this specific area of the intestine. They afford new data on the compartmentalization of the IIS, which have to be considered carefully to avoid erroneous conclusions.

In conclusion, GF, and gnotobiotic animal models are very useful tools to gain new insight into the fundamental role played by the intestinal microbiota on the complete activation of the IIS, with functional consequences. In certain aspects, adult GF mice, in which the IIS is poorly developed, may be considered as similar to that of the neonate and immunological immaturity of neonates can be questioned.

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