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Dendritic Cell-Intrinsic Expression of NF-B1 Is Required to Promote Optimal Th2 Cell Differentiation¹

Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104

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-B1 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-B1^–/– hosts failed to express Th2 cytokines and developed a polarized Ag-specific IFN- response. In an in vivo adoptive transfer model in which NF-B-sufficient OVA-specific DO11.10 TCR transgenic T cells were injected into OVA-immunized WT or NF-B1^–/– hosts, NF-B1^–/– APCs efficiently promoted CD4⁺ T cell proliferation and IFN- responses, but failed to promote Ag-specific IL-4 production. Further, bone marrow-derived DC from NF-B1^–/– mice failed to promote OVA-specific Th2 cell differentiation in in vitro coculture studies. Last, S. mansoni egg Ag-pulsed NF-B1^–/– DC failed to prime for Th2 cytokine responses following injection into syngeneic WT hosts. Impaired Th2 priming by NF-B1^–/– 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-B1 in regulating the MAPK pathway and governing the competence of DC to instruct Th2 cell differentiation.

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