title: Differentiation of inflammatory dendritic cells is mediated by NF-κB1-dependent GM-CSF production in CD4 T cells.
abstract: Rel/NF-κB transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-κB1-deficient (Nfkb1(-/-)) mice were profoundly protected from sterile CD4 T cell-dependent acute inflammatory arthritis and peritonitis. We evaluated CD4 T cell function in Nfkb1(-/-) mice and found increased apoptosis and selectively reduced GM-CSF production. Apoptosis was blocked by expression of a Bcl-2 transgene without restoring a disease response. In contrast with wild-type cells, transfer of Nfkb1(-/-) or GM-CSF-deficient CD4 T cells into RAG-1-deficient (Rag1(-/-)) mice failed to support arthritis induction. Injection of GM-CSF into Nfkb1(-/-) mice fully restored the disease response, suggesting that T cells are an important source of GM-CSF during acute inflammation. In Ag-induced peritonitis, NF-κB1-dependent GM-CSF production in CD4 T cells was required for disease and for generation of inflammatory monocyte-derived dendritic cells (MoDC), but not conventional dendritic cells. MoDC were identified in inflamed synovium and draining lymph nodes during arthritis. These MoDC produced high levels of MCP-1, a potent chemoattractant for monocytes. This study revealed two important findings: NF-κB1 serves a critical role in the production of GM-CSF by activated CD4 T cells during inflammatory responses, and GM-CSF derived from these cells drives the generation of MoDC during inflammatory disease.
authors.affiliation: Reid Rheumatology Laboratory, Division of Inflammation, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Ian K
authors.initials: IK
authors.lastname: Campbell
authors.forename: Annemarie
authors.initials: A
authors.lastname: van Nieuwenhuijze
authors.forename: Elodie
authors.initials: E
authors.lastname: Segura
authors.forename: Kristy
authors.initials: K
authors.lastname: O'Donnell
authors.forename: Elise
authors.initials: E
authors.lastname: Coghill
authors.forename: Mirja
authors.initials: M
authors.lastname: Hommel
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.forename: José A
authors.initials: JA
authors.lastname: Villadangos
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000276:immunology* / Q000378:metabolism
chemical_list: D052002:NF-kappa B p50 Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor