Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q

Yoshizaki, Mariko; Tazawa, Aya; Kasumi, Eiji; Sasawatari, Shigemi; Itoh, Kenji; Dohi, Taeko; Sasazuki, Takehiko; Inaba, Kayo; Makrigiannis, Andrew P.; Toyama–Sorimachi, Noriko

doi:10.1182/blood-2008-12-192344

Cited by 29 publications

(40 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, we have reported that Ly49Q colocalizes with CpG ODN in the endosome/lysosome compartment of peritoneal macrophages and the murine macrophage cell line RAW264 (23). This colocalization appears to be crucial for intracellular trafficking of CpG ODN and TLR9 and cytokine production in response to CpG ODN (23). The present study confirms and extends these findings by demonstrating the critical function of the Ly49Q cytoplasmic domain ITIM in the regulation of IFN-a production by pDC through Tg complementation.…”

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 84%

“…Macrophages and pDC lacking Ly49Q showed altered distribution of TLR9 and CpG ODN (23). In particular, CpG ODNinduced tubular endolysosomal extension was impaired in the absence of Ly49Q.…”

Section: Colorimetric Reporter Cell Assay and Class I Mhc (Mhc-i) Tetmentioning

confidence: 97%

“…In macrophages and pDC, TLR9 and CpG distribution is altered in the absence of Ly49Q (23). A recent study proposed a role for KIR3DL2 in uptake and trafficking of CpG ODN in NK cells (47).…”

Section: Evidence For a Possible Role Of Ly49q In Cpg Odn Traffickingmentioning

confidence: 99%

See 3 more Smart Citations

Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine–Based Inhibitory Motif–Dependent Manner

Rahim

Tai

Troke

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4+ T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell–triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 84%

“…Macrophages and pDC lacking Ly49Q showed altered distribution of TLR9 and CpG ODN (23). In particular, CpG ODNinduced tubular endolysosomal extension was impaired in the absence of Ly49Q.…”

Section: Colorimetric Reporter Cell Assay and Class I Mhc (Mhc-i) Tetmentioning

confidence: 97%

Section: Evidence For a Possible Role Of Ly49q In Cpg Odn Traffickingmentioning

confidence: 99%

See 2 more Smart Citations

Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine–Based Inhibitory Motif–Dependent Manner

Rahim

Tai

Troke

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This mechanism is based on the different compartmentalization and retention time of TLR ligands within the endolysosomal pathway (14,16,39). According to this concept, TLR signaling in early endosomes (induced for example by A-type and C-type CpG DNA) is coupled with production of type I IFN, whereas signaling from late endosomes (induced for example by B-type and C-type CpG DNA) is coupled with cell differentiation and production of proinflammatory cytokines (14).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Fails To Activate NF-κB Signaling in Plasmacytoid Dendritic Cells

Dental

Florentin

Aouar

et al. 2012

J Virol

View full text Add to dashboard Cite

Plasmacytoid dendritic cells (pDCs) respond to viral infection by production of alpha interferon (IFN-␣P lasmacytoid dendritic cells (pDCs) are a highly specialized subset of dendritic cells that function as sentinels for viral infection and are responsible for production of type I interferons (IFN), proinflammatory cytokines, and antigen presentation during viral infection (15,19,32). pDCs are able to detect the genetic material of viruses with a subset of Toll-like receptors (TLR) localized to the endosomal compartment (10). These nucleotidesensing TLRs include TLR7 and TLR8, which recognize singlestranded RNA, and TLR9, which recognizes DNA. TLR7 also recognizes synthetic imidazoquinoline components, for example R848 (resiquimod), whereas TLR9 recognizes synthetic CpG oligonucleotides, for example CpG-A or CpG-B. Ligation of TLR7 and TLR9 with their agonists triggers a signaling cascade, which starts with recruitment of the MyD88 adaptor molecule to the cytoplasmic domain of nucleotide-sensing TLR. This activates the assembly of a multiprotein signal-transducing complex in the cytoplasm that includes interferon-regulatory factor 7 (IRF7) (10). Activated IRF7, which is constitutively expressed in pDCs, translocates to the nucleus and initiates the transcription of type I IFN.The elimination of hepatitis C virus (HCV) in more than 50% of chronically infected patients by treatment with alpha interferon (IFN-␣) (9, 20) suggests that pDCs can play an important role in the control of HCV infection. Several reports have shown that exposure of pDCs from healthy donors to HCV particles results in no or only weak production of type I IFN and cell differentiation (4,7,11,13,31). A recent report has shown that pDCs exposed in direct cell-to-cell contact with HCV-infected hepatoma cells, unlike those exposed to cell-free HCV virions, produce large amounts of type I IFN via TLR7 signaling (35). This suggests that pDCs could be responsible for production of intrahepatic type I IFN (17, 35). Importantly, these events require viral RNA replication but not virion formation in the stimulator cells. In parallel to IRF7-mediated production of IFN-␣, MyD88 signaling also leads to activation of nuclear factor kappa B (NF-B) and mitogenactivated protein kinases (MAPKs). Both NF-B and MAPKs stimulate secretion of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor ␣ (TNF-␣) and stimulate expression of costimulatory molecules such as CD80 and CD86. Recent reports have identified a new signaling pathway induced by TLR7 and dependent on PI3K-p38MAPK, which stimulates the early IFN-inducible genes MxA and CXCL10 and the TNF-related apoptosis-inducing ligand (TRAIL) in the absence of type I IFN (6, 27).To better understand the molecular mechanism of HCV sensing, we investigated whether exposure of pDCs to HCV-infected hepatoma cells induces not only IRF7 signaling but also NF-B signaling pathways necessary for pDC functions. We demonstrate that in comparison to influenza virus or synthetic agonists of TLR7 and TLR...

show abstract

Immune inhibitory receptors: Essential regulators of phagocyte function

Steevels

Meyaard

2011

Eur J Immunol

View full text Add to dashboard Cite

Phagocytes, including neutrophils, monocytes, and macrophages, play a crucial role in host defense by recognition and elimination of invading pathogens. Phagocytic cells produce reactive oxygen species (ROS), inflammatory cytokines, and chemokines, leading to bacterial killing and to recruitment and activation of additional immune cells. However, inflammatory mediators are potentially harmful for the host and their production is therefore tightly controlled by multiple regulatory mechanisms. One such mechanism is immune suppression by immune inhibitory receptors, which are increasingly acknowledged as potent regulators of the immune response. So far, research has focused on the role of these receptors in the regulation of NK cells, B cells, and T cells. Importantly, an accumulating number of inhibitory receptors have been identified on phagocytes. Here, we review the role of inhibitory receptors in the regulation of phagocyte cytokine production, migration, apoptosis, ROS production, and phagocytosis. Furthermore, we discuss the intracellular mechanisms utilized by distinct inhibitory receptors to regulate specific phagocyte functions. We demonstrate that inhibitory receptors are important regulators of the immune response, which bacteria can use to their advantage.

show abstract

Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q

Cited by 29 publications

References 36 publications

Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine–Based Inhibitory Motif–Dependent Manner

Ly49Q Positively Regulates Type I IFN Production by Plasmacytoid Dendritic Cells in an Immunoreceptor Tyrosine–Based Inhibitory Motif–Dependent Manner

Hepatitis C Virus Fails To Activate NF-κB Signaling in Plasmacytoid Dendritic Cells

Immune inhibitory receptors: Essential regulators of phagocyte function

Contact Info

Product

Resources

About