Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine.
Bottom Line: The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens.The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T(H)17 T cells.Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs.
Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.Show MeSH
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Mentions: Periodic acid-Schiff (PAS) staining of mucin in sections of small intestine (Fig. 2a) produced a goblet cell (GC) staining pattern similar in frequency, distribution, and dimensions to the dextran columns identified by 2P microscopy (Fig. 2b and c). Furthermore, in contrast to the acellular and impermeable discontinuities seen in the small intestine epithelium11, dextran columns were associated with a nucleus (Fig. 2d; Supplementary Fig. 2a; Supplementary Movie 3). To determine if the dextran filled cells were in fact GCs, sections of intestine from mice given lysine-fixable dextran were stained with antibodies to mucin 2 (MUC2) and cytokeratin 18, which are both highly expressed by GCs12. Dextran columns , showed near prefect co-localization with MUC2+ and cytokeratin 18+ epithelial cells displaying GC morphology (Fig. 2e, f). Therefore, we term this phenomenon “goblet cell-associated antigen passages” (GAPs). To address the possibility that GAPs are apoptotic GCs, we co-stained for various markers of apoptosis including cleaved cytokeratin 18, cleaved caspase 3, and TUNEL (Supplementary Fig 3 a–i). In all cases, we found no association between apoptotic GCs and GAPs. Moreover, GAPs are distinct from villous M-cells, since they did not co-localize with the M-cell marker glycoprotein 2 (GP2) (Fig. 2g)13. The frequency and distribution of GAPs assessed by 2P microscopy was similar in all strains of specific-pathogen-free (SPF) mice examined (supplementary Fig. 2 b–d), with a non-significant trend more GAPs detected in the terminal ileum (supplementary Fig. 2h). GAPS were also evident in human jejunum resection specimens (Fig. 2h, i), suggesting that GAPs are a general phenomenon of the healthy small intestine. We examined the frequency of GAPs in C3H/HejBir IL-10−/− mice14, which develop spontaneous intestinal inflammation with GC loss, and in germ-free (GF) mice that lack normal gut flora. The number of GAPs and GCs correlated strongly; GAPs and GCs were significantly more numerous in GF mice (supplementary Fig. 2 e and g) and significantly fewer in IL-10−/− mice (supplementary Fig. 2 f and g).
Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.