MyD88-dependent TLR signals are necessary and sufficient to confer dendritic cells with gut-specific imprinting properties. (161.2)

Abstract Lymphocyte migration is at the heart of normal and pathological immune responses in the intestinal mucosa. We and others have shown that, in addition to activating lymphocytes, gut-associated dendritic cells (GALT-DC) can metabolize dietary vitamin A into all-trans retinoic acid (RA), which is required for inducing gut-tropic lymphocytes and IgA antibody-secreting cells (IgA-ASC). GALT-DC from mice deficient in the intracellular signaling adaptor MyD88, which lack most Toll-like receptor (TLR) signals, were significantly impaired in their capacity to induce gut-homing T cells and IgA-ASC and expressed low levels of retinal dehydrogenases (RALDH), which are critical enzymes for RA biosynthesis. MyD88-/- mice were also impaired in generating gut-tropic T cells upon immunization and exhibited low numbers of intestinal IgA-ASC. Pre-treatment of murine spleen-DC and human monocyte-derived DC with a TLR1/2 agonist was sufficient to induce RALDH and to confer these extra-intestinal DC with the capacity to induce gut-homing lymphocytes and IgA-ASC via a mechanism dependent on MyD88 and c-JNK/MAPK. Thus, MyD88-dependent TLR signals are both necessary and sufficient to educate DC with gut-specific imprinting properties.