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. 2006 Dec;119(4):470-8.
doi: 10.1111/j.1365-2567.2006.02458.x. Epub 2006 Sep 21.

Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse

Amanda M Williams  1 , Christopher S J Probert, Renata Stepankova, Helena Tlaskalova-Hogenova, Anne Phillips, Paul W Bland
Affiliations

Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse

Amanda M Williams et al. Immunology. 2006 Dec.

Abstract

Colonization with commensal flora in very early life may profoundly influence intestinal lymphoid development and bias later immune responses. We defined gut-homing T cell phenotypes and the influence of flora on intestinal immune development in mice. Intestinal T cells were phenotyped and quantified in conventional (CV), germfree (GF) and conventionalized germfree (GF/CV) neonatal mice by immunohistochemistry. Mucosal adressin cell adhesion molecule 1 (MAdCAM-1) was expressed by mucosal vessels at birth in CV and GF mice and was more prevalent in CV than GF small intestine, but was distributed similarly and did not change with age. Less MAdCAM-1 was expressed in the colon; its distribution became restricted after weaning, with no difference between CV and GF mice. CD3(+)beta(7) (+) cells were present in similar numbers in CV and GF intestine at birth. They were CD62L(-) in CV mice and were accompanied by further CD3(+)beta(7) (+)CD62L(-) T cells as development progressed, but in GF and GF/CV intestine they expressed CD62L and numbers did not change. IEL numbers increased at weaning in CV mice in both small and large intestine, but showed delayed development in GF intestine. Macrophages were present at high levels from birth in GF intestine, but dendritic cells did not develop until day 16. Thus, fetus-derived T cells seed the intestinal lamina propria before birth via beta-MadCAM interactions. Their activation status depends on the microbiological status of the dam, and without a commensal flora they remain naive. We propose that these cells regulate antigen responsiveness of the developing mucosal T cell pool.

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Figures

Figure 1
Figure 1
Distribution of mucosal adressin cell adhesion molecule 1 (MAdCAM-1) in small and large intestine of conventional (CV) and germfree (GF) mice before and after weaning. The distribution (a,b) and quantity (c,d) of MAdCAM-1 expressed by mucosal vasculature in small intestine and large intestine were determined in digitized images of tissues stained by immunofluorescence. Open boxes, GF; shaded boxes, CV. Horizontal bar, median; box, interquartile range; whiskers, extreme range; o, ordinary outlier (1·5–3 box lengths from lower part of box). *P < 0·05; **P <0·01; NS, not significantly different.
Figure 2
Figure 2
Representative images defining mucosal adressin cell adhesion molecule 1 (MAdCAM-1) expression (arrowheads) in conventional (CV, a) and germfree (GF, b) mouse small intestine at 10 days after birth.
Figure 3
Figure 3
Lamina propria T cell development in small and large intestine of young mice, expressed as total CD3+ cell frequency (a,b), CD3+α4β7+ double positive frequency (c,d), and frequency of α4β7 expression within the CD3+ cell population (e,f). Tissues were double-stained for CD3 and β7 and frequencies determined by image analysis. Open boxes, germfree (GF); dark shaded boxes, conventional (CV); light shaded boxes, conventionalized germfree (GF/CV). Horizontal bar, median; box, interquartile range; whiskers, extreme range; o, ordinary outlier (1·5–3 box lengths above or below box); small star, extraordinary outlier (> 3 box lengths above or below box) *P < 0·05; **P < 0·01; NS, not significantly different.
Figure 4
Figure 4
Frequency of CD3+ lamina propria cells co-expressing CD62L (l-selectin) in the small and large intestine of conventional (CV), germfree (GF) and conventionalized germfree (GF/CV) mice. Open boxes, GF; dark shaded boxes, CV; light shaded boxes, GF/CV. Horizontal bar, median; box, interquartile range; whiskers, extreme range; o, ordinary outlier (1·5–3 box lengths above or below box); small star, extraordinary outlier (> 3 box lengths above or below box) *P < 0·05; **P < 0·01; NS, not significantly different.
Figure 5
Figure 5
Intraepithelial CD3+ cells during development in conventionalized (CV) and germfree (GF) mouse small and large intestine. Open boxes, GF; dark shaded boxes, CV. Horizontal bar, median; box, interquartile range; whiskers, extreme range; o, ordinary outlier (1·5–3 box lengths above or below box); small star, extraordinary outlier (> 3 box lengths above or below box). *P < 0·05; **P < 0·01; NS, not significantly different.
Figure 6
Figure 6
Myeloid cell phenotype in the developing germfree (GF) mouse gut. Representative images of small intestine (left) and large intestine (right) stained for CD45 (a), F4/80 (b) or CD11c (c) at the ages shown. Arrowhead, isolated lymphoid follicle.
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