Distinct contributions of different CD40 TRAF binding sites to CD154-induced dendritic cell maturation and IL-12 secretion.
The mechanisms by which CD40 controls the maturation and antigen presentation functions of dendritic cells (DC) remains largely undefined in this critical cell type. To examine this question, we have employed retroviral transduction of primary bone marrow-derived mouse DC. Mutation of the distinct binding sites for TNF receptor-associated factor 6 (TRAF6) and for TRAF 2, 3, and 5 in the CD40 cytoplasmic domain revealed their independent contributions to DC maturation and activation of NF-kappaB. In contrast, disruption of the TRAF6 but not the TRAF 2,3,5 binding site markedly decreased IL-12 p40 secretion along with p38 and JNK activation in response to CD154 stimulation. These data document a clear bifurcation of the CD40 signaling cascade in primary DC at the level of the receptor's two distinct and autonomous TRAF binding sites, and reveal the predominant role of the TRAF6 binding site in CD40-induced pro-inflammatory cytokine production by these cells.
Mackey
Matthew F
MF
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive MSC-1892, Bethesda, MD 20892-1892, USA. matthew.mackey@aventis.com
Wang
Ze
Z
Eichelberg
Katrin
K
Germain
Ronald N
RN
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019013:CD40 Antigens / Q000737:chemistry / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D002352:Carrier Proteins; D016328:NF-kappa B; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand; D018664:Interleukin-12; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases