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Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways.

  • Author(s): Shih, Vincent F-S
  • Davis-Turak, Jeremy
  • Macal, Monica
  • Huang, Jenny Q
  • Ponomarenko, Julia
  • Kearns, Jeffrey D
  • Yu, Tony
  • Fagerlund, Riku
  • Asagiri, Masataka
  • Zuniga, Elina I
  • Hoffmann, Alexander
  • et al.

Published Web Location

https://doi.org/10.1038/ni.2446
Abstract

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses.

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