核酸刺激樹状細胞におけるI型インターフェロン産生制御機構

TLRs are able to recognize a variety of immune adjuvants. These adjuvants can be categorized into lipids, proteins, and nucleic acids according to their molecular characteristics. TLRs are able to transduce common immunostimulatory signals, but each TLR is also able to exhibit its own function.  We are attempting to clarify how TLRs exert their pleiotropic functions, especially on DCs. Notably, nucleic acid adjuvants are featured by their ability to induce type I interferons(IFNs), especially IFN-alpha. Single stranded RNA (ssRNA) and CpG DNA function as the ligands for TLR7 and TLR9, respectively. TLR7- and TLR9-induced IFN-alpha production depends on a DC subset, called as plasmacytoid dendritic cells (PDCs) (Fig.1). PDC can be distinguished from conventional DC (cDC) according to the surface molecule expression. PDC expresses only TLR7 and TLR9 among TLRs and, by sensing virus-derived nucleic acids, plays vital roles in antiviral immunity as a type I IFN producing cell.

Nucleic acid-induced type I IFN production also contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE). In those patients, anti-nucleic acid Abs are generated and form complexes with host-derived nucleic acids. Those complexes can induce type I IFNs. Indeed, in the patients, serum type I IFN levels are elevated and the elevation is correlated with the severity of the diseases.

All TLR7/9-mediated effects, inlcluding induction of both inflammatory cytokines and type I IFNs, are dependent on a TLR-associated cytoplasmic adapter, MyD88. Downstream of MyD88, the signaling pathway is bifurcated into two pathways for inflammatory cytokine and type I IFN induction. The former pathway depends on NF-kappaB and the latter pathway, specific for PDC, requires a transcription factor, IRF-7.

We have identified IKKalpha as a critical kinase selectively involved in this We have identified IKKalpha as a critical kinase selectively involved in this PDC-specific pathway (Fig.2). In IKKalpha-deficient mice, ability of PDC to produce IFN-alpha in response to TLR7/9 signaling is severely impaired. However, TLR7/9-induced production of inflammatory cytokines is mildly or marginally impaired. IKKalpha can associate with and phosphorylate IRF-7, thereby activating IRF-7 function. IKKalpha should be a candidate target molecule for treating autoimmune disorders.