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

ABSTRACT: The NF-?B 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-?B pathway, but as a RelB-p50 dimer regulated by canonical I?Bs, I?B? and I?B?. I?B control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-?B 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.

SUBMITTER: Shih VF 

PROVIDER: S-EPMC3634611 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Shih Vincent F-S VF   Davis-Turak Jeremy J   Macal Monica M   Huang Jenny Q JQ   Ponomarenko Julia J   Kearns Jeffrey D JD   Yu Tony T   Fagerlund Riku R   Asagiri Masataka M   Zuniga Elina I EI   Hoffmann Alexander A  

Nature immunology 20121021 12

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 co  ...[more]

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