title: Dendritic cell maturation and survival are differentially regulated by TNFR1 and TNFR2.
abstract: The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNFR, TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c(+) DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86, and HLA-DR) as well as enhanced T cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death, indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NF-κB signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65, activation. Accordingly, the p65 NF-κB pathway only played a role in the prosurvival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-xL pathway. Taken together, our data show that TNFR1, but not TNFR2, signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and they demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways.
authors.affiliation: Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Maney
authors.affiliation: Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Reynolds
authors.affiliation: Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Krippner-Heidenreich
authors.affiliation: Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Catharien M U
authors.initials: CMU
authors.lastname: Hilkens
mesh_terms: D056704:Adaptive Immunity; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; D015415:Biomarkers; D006684:HLA-DR Antigens; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D052003:NF-kappa B p52 Subunit; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D000097802:CD83 Antigen; C494811:BCL2L1 protein, human; C497964:CD86 protein, human