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-κB1 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-κB1-/- hosts failed to express Th2 cytokines and developed a polarized Ag-specific IFN-γ response. In an in vivo adoptive transfer model in which NF-κB-sufficient OVA-specific DO11.10 TCR transgenic T cells were injected into OVA-immunized WT or NF-κB1-/- hosts, NF-κB1-/- APCs efficiently promoted CD4+ T cell proliferation and IFN-γ responses, but failed to promote Ag-specific IL-4 production. Further, bone marrow-derived DC from NF-κB1-/- mice failed to promote OVA-specific Th2 cell differentiation in in vitro cocultare studies. Last, S. mansoni egg Ag-pulsed NF-κB1-/- DC failed to prime for Th2 cytokine responses following injection into syngeneic WT hosts. Impaired Th2 priming by NF-κB1-/- 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-κB1 in regulating the MAPK pathway and governing the competence of DC to instruct Th2 cell differentiation.
|Number of pages||6|
|Journal||Journal of Immunology|
|Publication status||Published - 1 Jun 2005|