title: MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota.
abstract: Intestinal homeostasis and induction of systemic tolerance to fed Ags (i.e., oral tolerance) rely on the steady-state migration of small intestinal lamina propria dendritic cells (DCs) into draining mesenteric lymph nodes (MLN). The majority of these migratory DCs express the α integrin chain CD103, and in this study we demonstrate that the steady-state mobilization of CD103(+) DCs into the MLN is in part governed by the IL-1R family/TLR signaling adaptor molecule MyD88. Similar to mice with complete MyD88 deficiency, specific deletion of MyD88 in DCs resulted in a 50-60% reduction in short-term accumulation of both CD103(+)CD11b(+) and CD103(+)CD11b(-) DCs in the MLN. DC migration was independent of caspase-1, which is responsible for the inflammasome-dependent proteolytic activation of IL-1 cytokine family members, and was not affected by treatment with broad-spectrum antibiotics. Consistent with the latter finding, the proportion and phenotypic composition of DCs were similar in mesenteric lymph from germ-free and conventionally housed mice. Although TNF-α was required for CD103(+) DC migration to the MLN after oral administration of the TLR7 agonist R848, it was not required for the steady-state migration of these cells. Similarly, TLR signaling through the adaptor molecule Toll/IL-1R domain-containing adapter inducing IFN-β and downstream production of type I IFN were not required for steady-state CD103(+) DC migration. Taken together, our results demonstrate that MyD88 signaling in DCs, independently of the microbiota and TNF-α, is required for optimal steady-state migration of small intestinal lamina propria CD103(+) DCs into the MLN.
authors.affiliation: Immunology Section, Lund University, 221 84 Lund, Sweden;
authors.forename: Karin
authors.initials: K
authors.lastname: Hägerbrand
authors.affiliation: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Westlund
authors.affiliation: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Center, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden; and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Yrlid
authors.affiliation: Immunology Section, Lund University, 221 84 Lund, Sweden; Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1870 Frederiksberg C, Denmark.
authors.forename: William
authors.initials: W
authors.lastname: Agace
authors.affiliation: Immunology Section, Lund University, 221 84 Lund, Sweden; bengt.johansson_lindbom@med.lu.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Johansson-Lindbom
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D039001:Integrin alpha Chains / Q000096:biosynthesis / Q000378:metabolism*; D016899:Interferon-beta / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D039481:CD11b Antigen; D020170:Caspase 1; D007093:Imidazoles; D039001:Integrin alpha Chains; D016899:Interferon-beta; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C477038:Tlr7 protein, mouse; C091367:alpha E integrins; C402365:resiquimod