A20 DC SUBSETS · Immune regulation of NF-kappaB in Dendritic Cell subsets by the ubiquitin editing enzyme A20

Dendritic cells (DCs) are strategically positioned as sentinels that process antigens and present these to other immune cells, thereby acting as crucial messengers between innate and adaptive immunity. DCs are activated by various receptors, including Toll-like receptors (TLRs) that recognize microbial products. TLR stimulation leads to activation of the transcription factor NF-κB, which is the key regulator of pro-inflammatory genes. NF-κB activation is tightly regulated by ubiquitination, a modification process that targets proteins for proteasomal degradation. The most important negative regulator of NF-κB activation is the ubiquitin-modifying enzyme A20/Tnfaip3. We have recently established an in vivo constitutive NF-κB activation mouse model system by DC-specific A20 gene ablation (using the Cre/loxP system). Our preliminary results demonstrate that A20 in DCs critically controls inflammation in the context of allergy and autoimmunity. Consistent with defective termination of TLR/NF-κB signalling, we found that A20KO DCs manifest an activated phenotype and DC-A20KO mice exhibit increased inflammation and high levels of serum autoantibodies. Remarkably however, DC-A20KO mice are protected from allergic asthma and experimental autoimmune encephalomyelitis. The proposal will provide fundamental knowledge on the effects of NF-κB activation in different DC subsets and should offer a starting point for therapies for inflammatory diseases based on ubiquitin modification.