Dendritic cell-intrinsic expression of NF-κB1 is required to promote optimal Th2 cell differentiation

David Artis, Colleen M. Kane, James Fiore, Colby Zaph, Sagi Shapira, Karen Joyce, Andrew MacDonald, Christopher Hunter, Phillip Scott, Edward J. Pearce

Research output: Contribution to journalArticleResearchpeer-review

44 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)7154-7159
Number of pages6
JournalJournal of Immunology
Volume174
Issue number11
Publication statusPublished - 1 Jun 2005
Externally publishedYes

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