scholarly journals Plasmacytoid dendritic cell–derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 1949-1957 ◽  
Author(s):  
Deepa Rajagopal ◽  
Carine Paturel ◽  
Yannis Morel ◽  
Satoshi Uematsu ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Immune Activation ◽  
Plasmacytoid Dendritic Cell ◽  
Innate Immune ◽  
Type I ◽  
Toll Like Receptor ◽  
Adjuvant Activity ◽  
Innate Immune Activation ◽  
Tlr7 Agonist

Abstract There is a high demand for the development of adjuvants that induce cytotoxic T lymphocytes, which are crucial for the elimination of intracellular pathogens and tumor cells. Toll-like receptor (TLR) agonists are prime candidates to fulfill this role because they induce innate immune activation and promote adaptive immune responses. The successful application of the TLR7 agonist R837 for treatment of basal cell carcinoma shows the potential for exploiting this pathway in tumor immunotherapy. Imidazoquinolines like R837 and stimulatory ssRNA oligonucleotides both trigger TLR7-mediated immune activation, but little is known about their comparative ability to promote immunity induction. We investigated differences in innate immune activation and adjuvant activity between the imidazoquinoline R848 and the ssRNA TLR7 agonist polyUs21. In contrast to R848, polyUs21 induced detectable levels of intracellular interferon-α (IFN-α) in plasmacytoid dendritic cells (PDCs). In immunization studies, only polyUs21 led to robust priming of type 1 T helper cells and cytotoxic T lymphocytes, and it was more efficient in inducing antitumor immunity than R848. Notably, exogenous IFN-α augmented the adjuvant activity of R848, whereas depletion of PDC abrogated the adjuvanticity of polyUs21. This study, therefore, identifies sufficient IFN-α production by PDC as an important determinant of vaccine efficacy.

scholarly journals ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Maria Pujantell ◽  
Roger Badia ◽  
Iván Galván-Femenía ◽  
Edurne Garcia-Vidal ◽  
Rafael de Cid ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Immune Activation ◽  
Hpv Infection ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Activation ◽  
Enhanced Expression

AbstractInfection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1–24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.

Toll-Like Receptor and Autoimmunity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-24-SCI-24
Author(s):  
Mark Shlomchik ◽  
Kevin Nickerson ◽  
Rebecca Sweet ◽  
Sean Christensen ◽  
Robin Herlands
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Activation ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Autoreactive B Cells ◽  
Innate Immune Activation ◽  
Intrinsic Roles

Abstract Abstract SCI-24 While the paradigm that adaptive immunity to pathogens requires innate immune activation via pattern recognition receptors is well accepted, until recently how autoimmune responses are initiated and propagated has been less clear. In principle, it is less obvious how the requisite innate immune activation might occur. In 2002 landmark results demonstrated that autoreactive B cells could be activated in vitro by a self-Ags that contained both a BCR and a Toll-like receptor (TLR) ligand; the ability of endogenous chromatin antigens to engage TLR9, a DNA sensor, could explain how anti-DNA type antibodies were generated. We have extended these results in two ways. First, we have evaluated the roles of TLR9 and TLR7 (a ssRNA receptor) in vivo. We backcrossed TLR9 (DNA) and TLR7 (ssRNA) knockout alleles onto the MRL/lpr lupus-prone background. We found that TLR9 was required to generate the anti-chromatin response and TLR7 was required for anti-RNA associated responses. With respect to disease, TLR9 had an unexpected regulatory role: KO mice get more severe lupus, hypergammaglobulinemia, and die prematurely. Whereas, TLR7-deficient mice demonstrate ameliorated disease. This is surprising as TLR7 and TLR9 are highly homologous, are expressed in similar cells, and signal through the same pathway. To investigate the mechanism behind these differences, we have made TLR7 KO and TLR7/9 double KO MRL/lpr mice and I will discuss their phenotypes. In addition, we have used these animals to investigate B cell intrinsic roles for TLR9, and these data will be presented. These results suggest that innate immunity contributes to initiation and specificity of autoimmunity. In the second line of investigation, we have used a mouse that expresses an autoreactive BCR, specific for self-IgG (rheumatoid factor, RF) to investigate the roles of TLRs and T cells in the initial activation of these cells. Taken together, our results indicate that autoreactive B cells are activated in a TLR-dependent, T cell-independent fashion, but only by self molecules that provide a simultaneous BCR and TLR ligand. These cells then differentiate into autoantibody secreting plasmablasts and also are a vector for activating autoreactive T cells. Once this occurs, we propose that full-blown autoimmune disease is initiated and maintained by positive feedback between autoreactive B and T cells. The implications of this model for therapeutic approaches that target both B cells and TLRs will be discussed. Disclosures Shlomchik: Coley Pharmaceuticals: Patents & Royalties.

scholarly journals A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Mohammad Adnan Siddiqui ◽  
Akatsuki Saito ◽  
Upul D. Halambage ◽  
Damien Ferhadian ◽  
Douglas K. Fischer ◽  
...  
Keyword(s):  
Immune Activation ◽  
Innate Immune ◽  
Wild Type Virus ◽  
Type I ◽  
Dna Sensing ◽  
Viral Dna ◽  
Innate Immune Activation ◽  
Naturally Occurring ◽  
Capsid Stability ◽  
Hiv 1

ABSTRACTThe HIV-1 capsid executes essential functions that are regulated by capsid stability and host factors. In contrast to increasing knowledge on functional roles of capsid-interacting host proteins during postentry steps, less is known about capsid stability and its impact on intracellular events. Here, using the antiviral compound PF-3450074 (PF74) as a probe for capsid function, we uncovered a novel phenotype of capsid stability that has a profound effect on innate sensing of viral DNA by the DNA sensor cGAS. A single mutation, R143A, in the capsid protein conferred resistance to high concentrations of PF74, without affecting capsid binding to PF74. A cell-free assay showed that the R143A mutant partially counteracted the capsid-destabilizing activity of PF74, pointing to capsid stabilization as a resistance mechanism for the R143A mutant. In monocytic THP-1 cells, the R143A virus, but not the wild-type virus, suppressed cGAS-dependent innate immune activation. These results suggest that capsid stabilization improves the shielding of viral DNA from innate sensing. We found that a naturally occurring transmitted founder (T/F) variant shares the same properties as the R143A mutant with respect to PF74 resistance and DNA sensing. Imaging assays revealed delayed uncoating kinetics of this T/F variant and the R143A mutant. All these phenotypes of this T/F variant were controlled by a genetic polymorphism located at the trimeric interface between capsid hexamers, thus linking these capsid-dependent properties. Overall, this work functionally connects capsid stability to innate sensing of viral DNA and reveals naturally occurring phenotypic variation in HIV-1 capsid stability.IMPORTANCEThe HIV-1 capsid, which is made from individual viral capsid proteins (CA), is a target for a number of antiviral compounds, including the small-molecule inhibitor PF74. In the present study, we utilized PF74 to identify a transmitted/founder (T/F) strain that shows increased capsid stability. Interestingly, PF74-resistant variants prevented cGAS-dependent innate immune activation under a condition where the other T/F strains induced type I interferon. These observations thus reveal a new CA-specific phenotype that couples capsid stability to viral DNA recognition by cytosolic DNA sensors.

scholarly journals Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin

2005 ◽  
Vol 201 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Cevayir Coban ◽  
Ken J. Ishii ◽  
Taro Kawai ◽  
Hiroaki Hemmi ◽  
Shintaro Sato ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Activation ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Innate Immune Activation

Malaria parasites within red blood cells digest host hemoglobin into a hydrophobic heme polymer, known as hemozoin (HZ), which is subsequently released into the blood stream and then captured by and concentrated in the reticulo-endothelial system. Accumulating evidence suggests that HZ is immunologically active, but the molecular mechanism(s) through which HZ modulates the innate immune system has not been elucidated. This work demonstrates that HZ purified from Plasmodium falciparum is a novel non-DNA ligand for Toll-like receptor (TLR)9. HZ activated innate immune responses in vivo and in vitro, resulting in the production of cytokines, chemokines, and up-regulation of costimulatory molecules. Such responses were severely impaired in TLR9−/− and myeloid differentiation factor 88 (MyD88)−/−, but not in TLR2, TLR4, TLR7, or Toll/interleukin 1 receptor domain–containing adaptor-inducing interferon β−/− mice. Synthetic HZ, which is free of the other contaminants, also activated innate immune responses in vivo in a TLR9-dependent manner. Chloroquine (CQ), an antimalarial drug, abrogated HZ-induced cytokine production. These data suggest that TLR9-mediated, MyD88-dependent, and CQ-sensitive innate immune activation by HZ may play an important role in malaria parasite–host interactions.

scholarly journals Kinetics of Early Innate Immune Activation during HIV-1 Infection of Humanized Mice

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Jessica Katy Skelton ◽  
Ana Maria Ortega-Prieto ◽  
Steve Kaye ◽  
Jose Manuel Jimenez-Guardeño ◽  
Jane Turner ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Activation ◽  
Innate Immune ◽  
Model Systems ◽  
Humanized Mice ◽  
Type I ◽  
Innate Immune Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.

scholarly journals LPS-induced down-regulation of signal regulatory protein α contributes to innate immune activation in macrophages

2007 ◽  
Vol 204 (11) ◽  
pp. 2719-2731 ◽  
Author(s):  
Xiao-Ni Kong ◽  
He-Xin Yan ◽  
Lei Chen ◽  
Li-Wei Dong ◽  
Wen Yang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Immune Activation ◽  
Endotoxic Shock ◽  
Regulatory Protein ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Innate Immune Activation

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein (SIRP) α, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-κB signaling pathways. In addition, SIRPα can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRPα in innate immunity. We provide evidences that SIRPα is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRPα expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRPα expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRPα reduced macrophage responses to LPS. Knockdown of SIRPα caused prolonged activation of MAPKs and NF-κB pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRPα-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPα may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRPα functions as a biologically important modulator of TLR signaling and innate immunity.

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