TLR7 mediated viral recognition results in focal type I interferon secretion by dendritic cells

Shin-Ichiroh Saitoh,Takuma Shibata,Katsuaki Sato,Fumiko Abe,Ryutaro Fukui,Yorifumi Kikko,Kazuishi Kubota,Yoshiko Mori Saitoh,Hiroko Kozuka-Hata,Kenji Kontani,Natsuko Tanimura,Takeshi Ichinohe,Toshiaki Katada,Kensuke Miyake,Atsuo Kanno,Mayumi Hayashi,Masaaki Oyama

doi:10.1038/s41467-017-01687-x

Abstract

Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC–pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. Here we show that MyD88-dependent TLR7 signaling activates CD11a/CD18 integrin to induce microtubule elongation. TLR7+ lysosomes then become linked with these microtubules through the GTPase Arl8b and its effector SKIP/Plekhm2, resulting in perinuclear to peripheral relocalization of TLR7. The type I interferon signaling molecules TRAF3, IKKα, and mTORC1 are constitutively associated in pDCs. TLR7 localizes to mTORC1 and induces association of TRAF3 with the upstream molecule TRAF6. Finally, type I interferons are secreted in the vicinity of cell–cell contacts between clustered pDCs. These results suggest that TLR7 needs to move to the cell periphery to induce robust type I interferon responses in pDCs.

Highlights

Plasmacytoid dendritic cells sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC–pDC clusters, and produce type I interferons
CD11a/CD18 integrin is required for pDC IFN-α production
We found that polyU exposure induced pronounced clustering and polymerization of actin and microtubule in WT BM-pDCs but not their Tlr7−/−, Itgal−/−, or Myd88−/− counterparts (Fig. 1a–d)

Summary

Introduction

Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC–pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. PDC adhesion enhances expression of type I interferons[5, 6] and type I interferon production by pDCs is positively correlated with cell density[6]. Type I interferons are likely to activate cell adhesion molecules, and cell–cell contact, in turn, may enhance type I interferon signaling. IFN-α/β are distinct from proinflammatory cytokines in an additional requirement for signaling molecules; whereas MyD88, interleukin-1 receptor-associated kinase 4 (IRAK4), and a US pU b. AP3 facilitates interaction between signaling molecules TRAF3 and IRF713; why IFN-α/β induction requires TLR7/9 trafficking is not known

Methods

Results

Conclusion