Intestinal Dendritic Cell Subsets: Differential Effects of Systemic TLR4 Stimulation on Migratory Fate and Activation In Vivo

Abstract

Dendritic cells (DC) present peripheral Ags to T cells in lymph nodes, but also influence their differentiation (tolerance/immunity, Th1/Th2). To investigate how peripheral conditions affect DC properties and might subsequently regulate T cell differentiation, we examined the effects of a potent DC-activating, TLR-4-mediated stimulus, LPS, on rat intestinal and hepatic DC in vivo. Steady-state rat intestinal and hepatic lymph DC are αE2 integrinhigh (CD103) and include two subsets, signal regulatory protein α (SIRPα)hi/low, probably representing murine CD8αα−/+ DC. Steady-state lamina propria DC are immature; surface MHC class IIlow, but steady-state lymph DC are semimature, MHC class IIhigh, but CD80/86low. Intravenous LPS induced rapid lamina propria DC emigration and increased lymph DC traffic without altering SIRPαhigh/SIRPαlow proportions. CD80/86 expression on lymph or mesenteric node DC was not up-regulated after i.v. LPS. In contrast, i.v. LPS stimulated marked CD80/86 up-regulation on splenic DC. CD80/86 expression on intestinal lymph DC, however, was increased after in vitro culture with TNF-α or GM-CSF, but not with up to 5 μg/ml LPS. Steady-state SIRPαlow DC localized to T cell areas of mesenteric nodes, spleen, and Peyer’s patch, whereas SIRPαhigh DC were excluded from these areas. Intravenous LPS stimulated rapid and abundant SIRPαhigh DC accumulation in T cell areas of mesenteric nodes and spleen. In striking contrast, i.v. LPS had no effect on DC numbers or distribution in Peyer’s patches. Our results suggest that any explanation of switching between tolerance and immunity as well as involving changes in DC activation status must also take into account differential migration of DC subsets.

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

“…Migrating DC comprise three subsets with different frequencies in intestinal and hepatic lymph DC migrating from the gut and liver in rats comprise two phenotypically distinct subsets differing in expression of CD172a and CD4 [9,10]. Here we have further analyzed these subsets following their collection from the thoracic ducts of MLNX and CoeLNX rats.…”

“…For the intestine this is due to complete emptying of DC from the LP [9]. We have recently observed that feeding rats with R-848, a TLR7/8 ligand, also results in a dramatic but transient increase in the numbers of DC in intestinal and liver lymph ( [17] and unpublished observations).…”

“…We have shown that intravenous administration of the TLR4 ligand LPS results in increased numbers of DC exiting both the intestine and liver [9,18]. For the intestine this is due to complete emptying of DC from the LP [9].…”

“…To selectively study DC that are actively migrating from the gut or the liver, we collect these cells from thoracic ducts of rats that have previously been mesenteric or coeliac lymphadenectomised (MLNX and CoeLNX, respectively) [9]. This enables us to study, with minimal in vitro manipulation, DC that have very recently left the intestine or the liver.…”

Commensal bacteria and epithelial cross talk in the developing intestine

“…In the intestinal epithelium, DC singe stand sample antigens passing through M cells or directly from within the intestine by opening tight junctions between IECs and extending dendrites into the gut lumen [46]. Microbial stimulation through TLRs controls DC activation, maturation, and migration at least in part through NF-κB and MAPK-dependent mechanisms [47][48][49]. Intestinal DCs may retain ingested live commensal bacteria within them, migrate to the mesenteric lymph nodes, and induce secretory IgA production without systemic immune activation [50].…”