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Figure 4.

Flagellin-specific regulation of adaptive immunity. (a) Correlation between Toll ike receptor 5 (TLR5)-stimulatory activity and flagellin structure. Left panel: The model of Parish considers S. adelaide flagellin as a potent antigen that stimulates antibody responses in rats. By disturbing flagellin structure, antibody response is impaired but delayed-type hypersensitivity that reflects Th1 response is stimulated. In these experiments, animals were primed with native (orange bar) or modified flagellin molecules that imprint the immune response, boosted with native flagellin and then assayed for antibody or delayed-type hypersensitivity. Right panel: TLR5-stimulatory activity is lost when mutations and/or insertions disturb the conserved domain of flagellin as presented schematically by the decrease in nuclear factor (NF)– κB induction. (b) Flagellin-dependent activation of dendritic cells (DC). Mucosal DCs sending membrane protrusions in lumen are in direct contact with the bacteria. M cells (yellow) are specialized epithelial cells intestinal Peyer’s patch that transport and deliver luminal bacteria to subepithelial DCs. These DCs can directly be stimulated by flagellin released by bacteria. Flagellin induces DC maturation in a TLR5-, MyD88-, and NF-κB-dependent manner. In this model, TLR5 signalling stimulates DC to shape Th2-biased immunity via production of Th2-promoting or Th1-suppressing factors. Such a mechanism in combination with epithelial environment imprints DCs and lymphocytes with mucosal-specific immunity program. (c) The flagellin-specific epithelial pathway. The following scenario might support an activity of flagellin on adaptive immunity controlled by epithelium: (1) flagellin monomers released from flagellated bacteria activate nearby epithelial cells. TLR5 signalling can be induced either on apical or basolateral side of epithelial cells; (2) for a short period, epithelial cells produce CCL20 and pro-inflammatory mediators that recruit immature DCs and neutrophils, respectively, and factors that shape recruited DC in a mucosal-type DC (3) transient histological changes occurs in epithelia facilitating uptake of luminal bacteria by recruited DCs; (4) DC maturation in the stimulated mucosa is followed by migration and presentation of bacteria-derived antigens in draining lymphoid structures, thereby stimulating mucosa-specific responses. Capture of bacteria might result from additional changes on epithelial cells dependent or not on TLR5. These changes are illustrated on the right panel: (top) the disruption of epithelial barrier provide a portal of entry for bacteria, (middle) the recruited DCs displace tight junctions and send membrane protrusions in the lumen, and (bottom) the epithelial cells become transiently capable to transport particles like do M cells of Peyer’s patch.

Trends Microbiol.
doi: 10.1016/j.tim.2004.09.002.