MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties |
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Authors: | Wang Sen Villablanca Eduardo J De Calisto Jaime Gomes Daniel C O Nguyen Deanna D Mizoguchi Emiko Kagan Jonathan C Reinecker Hans-Christian Hacohen Nir Nagler Cathryn Xavier Ramnik J Rossi-Bergmann Bartira Chen Yi-Bin Blomhoff Rune Snapper Scott B Mora J Rodrigo |
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Affiliation: | Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. |
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Abstract: | Gut-associated dendritic cells (DC) synthesize all-trans retinoic acid, which is required for inducing gut-tropic lymphocytes. Gut-associated DC from MyD88(-/-) 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(-/-) 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(-/-) 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. |
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