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NF-κB signalling in dendritic cells

Dendritic cells (DCs) are the key components of the innate immune system, ready to be mobilised upon the first signs of infection. Comprehending DC biology is central for their therapeutic exploitation.
NF-κB signalling in dendritic cells
DCs serve as crucial messengers between innate and adaptive immunity by recognising specific molecular patterns found in bacteria, viruses, parasites, and fungi through pathogen-recognition receptors (PPRs). Triggering these receptors leads to the production of specific cytokines that in turn induce T cell differentiation. Central to the regulation of these cytokines is the activation and nuclear translocation of the key transcription factor NF-κB. The ubiquitin-modifying enzyme A20/TNFAIP3 in turn regulates signalling through NF-κB.

To further delineate the role of A20 in DC biology, the EU-funded A20 DC SUBSETS (Immune regulation of NF-kappaB in dendritic cell subsets by the ubiquitin editing enzyme A20) project performed next-generation RNA-sequencing of A20 knock-out (KO), heterozygous and wild-type (WT) DCs. Results showed a differential expression of nearly 2 000 genes involved in Th17-cell differentiation, B cell activation, neutrophil attraction and growth.

In vitro co-culture experiments of Th naïve cells with DCs showed that the lack of A20 skewed differentiation towards the Th17 lineage, while WT DCs induced Th2 cells.

Scientists investigated the effect of A20 deficiency in several DC subsets to discover a specific role for each subset in maintaining immune homeostasis. An interesting observation was made when A20 was deleted specifically in lung DCs in a model for allergic asthma and influenza infection. These animals were protected from Th2-associated immune responses, but were superior in clearing influenza infection compared to control mice.

Collectively, the work of the A20 DC SUBSETS provided fundamental insight into DC biology and the context-dependent importance of NF-κB signalling. The generated findings could serve as the basis for further analyses to understand key DC processes and design specific targeting strategies. The latter have the potential to lead to novel therapies for immune-driven diseases.

Related information

Keywords

NF-κB, dendritic cell, DC subsets, A20/TNFAIP3, T-cell
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