During Salmonella Typhimurium infection, intestinal CX₃CR1⁺ cells can either extend transepithelial cellular processes to sample luminal bacteria or, very early after infection, migrate into the intestinal lumen to capture bacteria. However, until now, the biological relevance of the intraluminal migration of CX₃CR1⁺ cells remained to be determined. We addressed this by using a combination of mouse strains differing in their ability to carry out CX₃CR1-mediated sampling and intraluminal migration. We observed that the number of S. Typhimurium traversing the epithelium did not differ between sampling-competent/migration-competent C57BL/6 and sampling-deficient/migration-competent BALB/c mice. In contrast, in sampling-deficient/migration-deficient CX₃CR1^-/- mice the numbers of S. Typhimurium penetrating the epithelium were significantly higher. However, in these mice the number of invading S. Typhimurium was significantly reduced after the adoptive transfer of CX₃CR1⁺ cells directly into the intestinal lumen, consistent with intraluminal CX₃CR1⁺ cells preventing S. Typhimurium from infecting the host. This interpretation was also supported by a higher bacterial fecal load in CX₃CR1^+/gfp compared with CX₃CR1^gfp/gfp mice following oral infection. Furthermore, by using real-time in vivo imaging we observed that CX₃CR1⁺ cells migrated into the lumen moving through paracellular channels within the epithelium. Also, we reported that the absence of CX₃CR1-mediated sampling did not affect Ab responses to a noninvasive S. Typhimurium strain that specifically targeted the CX₃CR1-mediated entry route. These data showed that the rapidly deployed CX₃CR1⁺ cell-based mechanism of immune exclusion is a defense mechanism against pathogens that complements the mucous and secretory IgA Ab-mediated system in the protection of intestinal mucosal surface.

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