Fig. 2

Molecular mechanisms of viral sensing by pDCs. pDCs sense viral nucleic acids through endosomal TLR7 and TLR9, which recognize single-stranded RNA rich in uridine and unmethylated CpG DNA, respectively. When endosomal TLR7/9 interact with their respective ligands, the MYD88-IRF7 signaling pathway is activated. This leads to the recruitment and phosphorylation of the transcription factor interferon regulatory Factor 7 (IRF7), which is translocated to the nucleus, where it induces transcription of the genes encoding IFN-α/β (IFN-Is) and IFN-λ (IFN-IIIs). Different viral recognition mechanisms have been proposed to promote pDC activation and trigger IFN production. Virus-derived nucleic acid contained in exosomes or apoptotic/necrotic bodies released from infected cells can be captured by pDCs and engulfed into endosomes ①. Free viruses can also be captured by pDCs via unknown receptors and activate them ②. Finally, pDCs can establish contact-dependent interactions with infected cells, generating an immune synapse involving adhesion molecules, such as LFA-1, which is expressed by pDCs, and ICAM-1, which is expressed by infected cells ③. The TNFR expressed by pDCs may also stabilize this synapse upon interaction with its ligand TNF, which can be expressed in a membrane-bound form at the surface of infected cells. As another source of TNF, pDCs may also amplify their own IFN production in an autocrine or paracrine response, but other TNF sources may also be involved. The stabilization of the immune synapse requires the polarization of the actin network in pDCs, which enables pDCs to capture viral material, the nature of which has not yet been elucidated and could vary depending on the nature of the virus and the infected cells