Similar to blood-enriched DCs, STp priming expanded ongoing production of regulatory IL-10 in human intestinal DCs (Figure 3a and 3b). Figure 3 STp primes human intestinal DC towards a regulatory phenotype. Since http://www.selleckchem.com/products/crenolanib-cp-868596.html resting intestinal DCs from healthy controls do not usually produce pro-inflammatory cytokines like IL-12 [28], there was no statistically significant inhibition of such cytokine although its ongoing production was blocked in DCs from the 3 healthy controls producing it (Figure 3c). Human intestinal DCs are less stimulatory than blood DCs and prime T-cells with a gut-homing profile [29]. STp conditioning did not alter the stimulatory capacity of intestinal DC (Figure 3d). Nevertheless, such intestinal STp-pulsed DCs induced more CLA expression on stimulated T-cells than basal intestinal DC.

IL-10 production by stimulated T-cells was also increased (Figure 3e�Cf). Recently, it has been proposed that the host has no capacity to distinguish between ��harmful�� and ��commensal�� microbiota, but the substrates that the microbiota produce actively promote immunologic tolerance to symbiotic bacteria [30]. Our data adds a new dimension to the concept of intestinal immune tolerance and shows that STp could be related not to the mechanisms of intestinal immune tolerance but rather of intestinal immune ignorance by diverting immune responses from the gastrointestinal compartment [10]. Therefore, in health, T-cells stimulated by bacteria-products-primed DC would be diverted away from intestinal sites to the skin.

Similar results highlighting the role of bacterial-derived products have been recently reported such as the role of immunomodulatory polysaccharide A from Bacteroides fragilis that mediated conversion of CD4+ T-cells into IL-10 producing T-cells [31], or the case of a soluble protein produced by L. rhamnosus GG, which prevented cytokine-induced apoptosis in intestinal epithelial cells [32]. Similarly, peptidoglycan of Lactobacilli was capable of inducing a regulatory phenotype on mouse intestinal DC [33] while probiotic bacterial DNA increases IL-10 production by DC, while DNA from non-probiotic bacteria failed to induce such regulatory phenotype on DC (Hart, AL; personal communication). Such evidence is in agreement with our findings and suggests that the crosstalk between the commensal microbiota and the local immune system is partially elicited through soluble factors and not exclusively through direct cell contact. To sum up, in the human gut L. plantarum secretes an extracellular protein that releases an internal fragment (STp) when cleaved by intestinal proteases. STp might thus interact with human AV-951 intestinal DCs in vivo promoting mechanisms of intestinal homeostasis.