scholarly journals STING: a master regulator in the cancer-immunity cycle

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuanyuan Zhu ◽  
Xiang An ◽  
Xiao Zhang ◽  
Yu Qiao ◽  
Tongsen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Negative Effects ◽  
Independent Manner ◽  
Adaptive Immune ◽  
Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

scholarly journals Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

2007 ◽  
Vol 81 (7) ◽  
pp. 3170-3180 ◽  
Author(s):  
Jiangao Zhu ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Adenoviral Vectors ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

scholarly journals Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami
Keyword(s):  
Immune Responses ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals The Molecular Interactions of ZIKV and DENV with the Type-I IFN Response

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 530
Author(s):  
Rosa C. Coldbeck-Shackley ◽  
Nicholas S. Eyre ◽  
Michael R. Beard
Keyword(s):  
Immune Responses ◽  
Molecular Interactions ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Control Measures ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Vaccination Strategies ◽  
Significant Disease

Zika Virus (ZIKV) and Dengue Virus (DENV) are related viruses of the Flavivirus genus that cause significant disease in humans. Existing control measures have been ineffective at curbing the increasing global incidence of infection for both viruses and they are therefore prime targets for new vaccination strategies. Type-I interferon (IFN) responses are important in clearing viral infection and for generating efficient adaptive immune responses towards infection and vaccination. However, ZIKV and DENV have evolved multiple molecular mechanisms to evade type-I IFN production. This review covers the molecular interactions, from detection to evasion, of these viruses with the type-I IFN response. Additionally, we discuss how this knowledge can be exploited to improve the design of new vaccine strategies.

scholarly journals Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Carol L. Vinton ◽  
Samuel J. Magaziner ◽  
Kimberly A. Dowd ◽  
Shelly J. Robertson ◽  
Emerito Amaro-Carambot ◽  
...  
Keyword(s):  
Immune Responses ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Zikv Infection ◽  
Adaptive Immune ◽  
Immunodeficiency Virus

ABSTRACT Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV+) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV+ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV+ RMs. IMPORTANCE Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection.

Identification of a Novel Toll-Like Receptor-Independent Immunoadjuvant Pathway That Depends upon Programmed Cell Death.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 775-775
Author(s):  
Kasper Hoebe ◽  
Edith Janssen ◽  
Bruce Beutler
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Immune Responses ◽  
Ultraviolet Light ◽  
Adaptive Immune Response ◽  
Type I ◽  
Toll Like Receptors ◽  
Adjuvant Effect ◽  
Tlr Signaling ◽  
Adaptive Immune

Abstract Molecules of microbial origin, and synthetic derivatives of these molecules, have long been used for their immuno-adjuvant effect, and as the key sensors of microbial infection, Toll-like receptors (TLRs) are thought to be essential for adjuvanticity. To the contrary, we now demonstrate the existence of a robust, TLR-independent pathway for adjuvant effect: one that is actually far stronger than the TLR-dependent pathway. Activation of Toll-like receptors (TLRs) and the subsequent production of cytokines such as type I interferon leads to the maturation of dendritic cells (DCs) with upregulation of MHC molecules and costimulatory molecules such as CD40, CD80 and CD86, allowing for optimal interaction between DCs and T-cells. We have determined that TLR signal transduction is minimally dependent upon two adapter proteins, MyD88 and TRIF. In compound homozygous mutant (DKO) mice that lack functional MyD88 and TRIF, there is complete abrogation of all TLR signaling. Such animals therefore comprise a unique model with which to study TLR-independent immune responses. We have now used DKO mice to determine whether an adaptive immune response can be obtained in the absence of TLR signaling. As expected, adjuvanticity obtained via “classical” microbial adjuvants such as complete Freund’s adjuvant or LPS was completely absent in DKO mice. However, subcutaneous administration of syngeneic murine cells expressing ovalbumin and rendered apoptotic by exposure to ultraviolet light resulted in a strong T-cell response in vivo, with impressive production of interferon-g by CD8+ cells and efficient killing of EL-4 cells that expressed CD8-specific OVA peptides, both in wildtype and DKO mice. Adjuvanticity was observed only in the context of apoptosis, in that living cells, not exposed to ultraviolet light before injection, induced little or no response. Moreover, the mixture of the protein antigen with apoptotic cells was insufficient to induce an adaptive immune response; rather, only cells that expressed the protein prior to induction of apoptosis were stimulatory. These results indicate the existence of a specific, cell death-dependent mechanism for adjuvanticity that is TLR-independent and induced by endogenous molecules. We propose that this new adjuvant pathway is of fundamental importance to immune responses at large. We believe that it is required for initiation of the adaptive immune response witnessed in the context of allograft rejection, graft-versus-host disease, and autoimmune diseases as well.

scholarly journals Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

2010 ◽  
Vol 84 (13) ◽  
pp. 6549-6563 ◽  
Author(s):  
Erin L. Lousberg ◽  
Cara K. Fraser ◽  
Michael G. Tovey ◽  
Kerrilyn R. Diener ◽  
John D. Hayball
Keyword(s):  
Immune Responses ◽  
Plasmacytoid Dendritic Cell ◽  
Type I Interferons ◽  
Interleukin 12 ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Fowlpox Virus ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.

scholarly journals Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I Interferons

2006 ◽  
Vol 80 (9) ◽  
pp. 4538-4545 ◽  
Author(s):  
Carolina B. López ◽  
Jacob S. Yount ◽  
Tamar Hermesh ◽  
Thomas M. Moran
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Adaptive Immunity ◽  
Sendai Virus ◽  
Cytotoxic T Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

ABSTRACT Adaptive immunity in response to virus infection involves the generation of Th1 cells, cytotoxic T cells, and antibodies. This type of immune response is crucial for the clearance of virus infection and for long-term protection against reinfection. Type I interferons (IFNs), the primary innate cytokines that control virus growth and spreading, can influence various aspects of adaptive immunity. The development of antiviral immunity depends on many viral and cellular factors, and the extent to which type I IFNs contribute to the generation of adaptive immunity in response to a viral infection is controversial. Using two strains (Cantell and 52) of the murine respiratory Sendai virus (SeV) with differential abilities to induce type I IFN production from infected cells, together with type I IFN receptor-deficient mice, we examined the role of type I IFNs in the generation of adaptive immunity. Our results show that type I IFNs facilitate virus clearance and enhance the migration and maturation of dendritic cells after SeV infection in vivo; however, soon after infection, mice clear the virus from their lungs and efficiently generate cytotoxic T cells independently of type I IFN signaling. Furthermore, animals that are unresponsive to type I IFN develop long-term anti-SeV immunity, including CD8+ T cells and antibodies. Significantly, this memory response is able to protect mice against challenge with a lethal dose of virus. In conclusion, our results show that primary and secondary anti-SeV adaptive immunities are developed normally in the absence of type I IFN responsiveness.

Longitudinal system-based analysis of transcriptional responses to type I interferons

2009 ◽  
Vol 38 (3) ◽  
pp. 362-371 ◽  
Author(s):  
D. J. Pappas ◽  
G. Coppola ◽  
P. A. Gabatto ◽  
F. Gao ◽  
D. H. Geschwind ◽  
...  
Keyword(s):  
T Cells ◽  
Translation Initiation Factor ◽  
Type I Interferons ◽  
Initiation Factor ◽  
Type I ◽  
Type I Ifn ◽  
Transcriptional Responses ◽  
Statistical Measures ◽  
Differential Responses ◽  
Ifn Treatment

Type I interferons (IFNs) are pleiotropic cytokines that modulate both innate and adaptive immune responses. They have been used to treat autoimmune disorders, cancers, and viral infection and have been demonstrated to elicit differential responses within cells, despite sharing a single receptor. The molecular basis for such differential responses has remained elusive. To identify the mechanisms underlying differential type I IFN signaling, we used whole genome microarrays to measure longitudinal transcriptional events within human CD4+ T cells treated with IFN-α2b or IFN-β1a. We identified differentially regulated genes, analyzed them for the enrichment of known promoter elements and pathways, and constructed a network module based on weighted gene coexpression network analysis (WGCNA). WGCNA uses advanced statistical measures to find interconnected modules of correlated genes. Overall, differential responses to IFN in CD4+ T cells related to three dominant themes: migration, antigen presentation, and the cytotoxic response. For migration, WGCNA identified subtype-specific regulation of pre-mRNA processing factor 4 homolog B and eukaryotic translation initiation factor 4A2, which work at various levels within the cell to affect the expression of the chemokine CCL5. WGCNA also identified sterile α-motif domain-containing 9-like ( SAMD9L) as critical in subtype-independent effects of IFN treatment. RNA interference of SAMD9L expression enhanced the migratory phenotype of activated T cells treated with IFN-β compared with controls. Through the analysis of the dynamic transcriptional events after differential IFN treatment, we were able to identify specific signatures and to uncover novel genes that may underpin the type I IFN response.

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