Dendritic Cells with Gut-Specific Imprinting MyD88-Dependent TLR1/2 Signals Educate

Gut-associated dendritic cells (DC) synthesize all-trans retinoic acid, which is required for inducing gut-tropic lymphocytes. Gut-associated DC from MyD88 2/2 mice, which lack most TLR signals, expressed low levels of retinal dehydrogenases (critical enzymes for all-trans retinoic acid biosynthesis) and were significantly impaired in their ability to induce gut-homing T cells. Pretreatment of extraintestinal DC with a TLR1/2 agonist was sufficient to induce retinal dehydrogenases and to confer these DC with the capacity to induce gut-homing lymphocytes via a mechanism dependent on MyD88 and JNK/MAPK. Moreover, gut-associated DC from TLR2 2/2 mice, or from mice in which JNK was pharmacologically blocked, were impaired in their education to imprint gut-homing T cells, which correlated with a decreased induction of gut-tropic T cells in TLR2 2/2 mice upon immunization. Thus, MyD88-dependent TLR2 signals are necessary and sufficient to educate DC with gut-specific imprinting properties and contribute in vivo to the generation of gut-tropic T cells. I n addition to their well-known role as APCs, dendritic cells (DC) can modulate immune responses in a tissue-specific manner (1). DC from Peyer's patches (PP-DC) promote the induction of Th2 T cell responses and IgA Ig class-switching (1). In addition, DC from Peyer's patches, mesenteric lymph nodes, and small intestine lamina propria (gut-associated DC), but not DC from extraintestinal sites, induce a high expression of the gut-homing receptors integrin a4b7 and chemokine receptor CCR9 on mouse and human T and B cells upon activation (2–5). The selective capacity of gut-associated DC to induce gut-tropic lym-phocytes is explained by their ability to metabolize vitamin A (retinol) into all-trans retinoic acid (RA) (3, 5, 6). RA is necessary and sufficient to imprint gut-homing lymphocytes, and it also potentiates the induction of gut-homing Foxp3 + regulatory T cells (Treg) while reciprocally inhibiting the development of Th17 cells in vitro (7–9). Gut-associated DC, but not peripheral extra-intestinal DC, express high levels of retinal dehydrogenases (RALDH), which are key enzymes for RA biosynthesis. However, it is unclear how these enzymes are specifically induced in gut-associated DC. We reasoned that bone marrow-derived un-committed DC (or their precursors) enter the intestine from the blood and then acquire their imprinting properties in response to local differentiation signal(s) that are present in the gut mucosa. Among those environmental cues, the gut is highly exposed to pathogen-associated molecular patterns derived from the intestinal microbiota, which are recognized by pathogen recognition receptors, the best characterized of which …