Distinct roles for the NF-kappaB1 and c-Rel transcription factors in the differentiation and survival of plasmacytoid and conventional dendritic cells activated by TLR-9 signals.
Reticuloendotheliosis viral oncogene homolog/nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Rel/NF-kappaB) activation is a ubiquitous outcome of engaging Toll-like receptors (TLRs), yet the cell-type-specific functions of this pathway in response to particular microbial signals remain poorly defined. Here we show that NF-kappaB1 and C-Rel, Rel/NF-kappaB proteins induced in conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) by cytosine-phosphate-guanosine (CpG) DNA, a TLR-9 ligand, serve markedly different functions in these DC subsets. With the exception of impaired interleukin-12 (IL-12) production, cultured Nfkb1(-/-)C-Rel(-/-) cDCs responded relatively normally to CpG DNA. In contrast, CpG-treated Nfkb1(-/-)C-Rel(-/-) pDCs, which were still able to produce type I interferon and regulated on activation normal T-cell expressed and secreted (RANTES), but not IL-6 or IL-12, failed to acquire an activated dendritic phenotype and underwent apoptosis. Although the TLR-9-mediated death of Nfkb1(-/-)C-Rel(-/-) pDCs, which coincided with a failure to up-regulate the prosurvival proteins B-cell lymphoma apoptosis regulator xL (Bcl-x(L)) and A1, was blocked by Bcl-2 transgene expression, this inhibition of apoptosis still failed to rescue the differentiation defects. This indicated that these NF-kappaB transcription factors independently regulate TLR-9-mediated pDC morphogenesis and survival. Collectively, these findings establish that NF-kappaB1 and c-Rel, while largely dispensable for TLR-9-induced cDC activation, are critical for regulating differentiation and survival programs during pDC activation.
O'Keeffe
Meredith
M
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Grumont
Raelene J
RJ
Hochrein
Hubertus
H
Fuchsberger
Martina
M
Gugasyan
Raffi
R
Vremec
David
D
Shortman
Ken
K
Gerondakis
Steve
S
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D019254:Genes, bcl-2 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000276:immunology*; D001356:Reticuloendotheliosis virus / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology
C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D009838:Oligodeoxyribonucleotides; D020569:Proto-Oncogene Proteins c-rel; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D051020:bcl-X Protein