title: Dendritic cell-intrinsic expression of NF-kappa B1 is required to promote optimal Th2 cell differentiation.
abstract: A number of receptors and signaling pathways can influence the ability of dendritic cells (DC) to promote CD4(+) Th type 1 (Th1) responses. In contrast, the regulatory pathways and signaling events that govern the ability of DC to instruct Th2 cell differentiation remain poorly defined. In this report, we demonstrate that NF-kappaB1 expression within DC is required to promote optimal Th2 responses following exposure to Schistosoma mansoni eggs, a potent and natural Th2-inducing stimulus. Although injection of S. mansoni eggs induced production of IL-4, IL-5, and IL-13 in the draining lymph node of wild-type (WT) mice, NF-kappaB1(-/-) hosts failed to express Th2 cytokines and developed a polarized Ag-specific IFN-gamma response. In an in vivo adoptive transfer model in which NF-kappaB-sufficient OVA-specific DO11.10 TCR transgenic T cells were injected into OVA-immunized WT or NF-kappaB1(-/-) hosts, NF-kappaB1(-/-) APCs efficiently promoted CD4(+) T cell proliferation and IFN-gamma responses, but failed to promote Ag-specific IL-4 production. Further, bone marrow-derived DC from NF-kappaB1(-/-) mice failed to promote OVA-specific Th2 cell differentiation in in vitro coculture studies. Last, S. mansoni egg Ag-pulsed NF-kappaB1(-/-) DC failed to prime for Th2 cytokine responses following injection into syngeneic WT hosts. Impaired Th2 priming by NF-kappaB1(-/-) DC was accompanied by a reduction in MAPK phosphorylation in Ag-pulsed DC. Taken together, these studies identify a novel requirement for DC-intrinsic expression of NF-kappaB1 in regulating the MAPK pathway and governing the competence of DC to instruct Th2 cell differentiation.
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, 19104, USA. dartis@vet.upenn.edu
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Kane
authors.forename: James
authors.initials: J
authors.lastname: Fiore
authors.forename: Colby
authors.initials: C
authors.lastname: Zaph
authors.forename: Sagi
authors.initials: S
authors.lastname: Shapira
authors.forename: Karen
authors.initials: K
authors.lastname: Joyce
authors.forename: Andrew
authors.initials: A
authors.lastname: Macdonald
authors.forename: Christopher
authors.initials: C
authors.lastname: Hunter
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation; D011498:Protein Precursors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012550:Schistosoma mansoni / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology*
chemical_list: D000947:Antigens, Helminth; D018984:Epitopes, T-Lymphocyte; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D014157:Transcription Factors; C073701:Nfkb1 protein, mouse; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases