Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-kappa B1-Dependent GM-CSF Production in CD4 T Cells

Campbell, IK; van Nieuwenhuijze, A; Segura, E; O&#39;Donnell, K; Coghill, E; Hommel, M; Gerondakis, S; Villadangos, JA; Wicks, IP

Author(s): Campbell, IK; van Nieuwenhuijze, A; Segura, E; O'Donnell, K; Coghill, E; Hommel, M; Gerondakis, S; Villadangos, JA; Wicks, IP;
Details: Publication Year 2011-05-01,Volume 186,Issue #9,Page 5468-5477
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
Abstract: Rel/NF-kappa B transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-kappa B1-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 wildtype 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-kappa B1-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-kappa B1 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. The Journal of Immunology, 2011, 186: 5468-5477.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: NF-KAPPA-B; COLONY-STIMULATING FACTOR; REL TRANSCRIPTION FACTORS; MOUSE LYMPHOID ORGANS; FACTOR-DEFICIENT MICE; IN-VIVO; RHEUMATOID-ARTHRITIS; DISTINCT ROLES; P50 HOMODIMERS; STEADY-STATE
Publisher's Version: https://doi.org/10.4049/jimmunol.1002923
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-05-01 12:00:00