Nucleic acid sensing by T cells initiates Th2 cell differentiation

Imanishi, Takayuki; Ishihara, Chitose; Badr, Mohamed E.l.Sherif G.adelhaq; Hashimoto-Tane, Akiko; Kimura, Yayoi; Kawai, Taro; Takeuchi, Osamu; Ishii, Ken J.; Taniguchi, Shun’ichiro; Noda, Tetsuo; Hirano, Hisashi; Brombacher, Frank; Barber, Glen N.; Akira, Shizuo; Saito, Takashi

doi:10.1038/ncomms4566

Cited by 38 publications

(35 citation statements)

References 52 publications

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“…IL-10 regulates innate and adaptive Th1 and Th2 responses (Huang et al, 2018). Released self-dsDNA from dying cells can directly stimulate CD4 T cells to induce Th2 cell differentiation and activation (Imanishi et al, 2014), but the role of M.tb DNA in this response was not investigated. Our in vivo studies also show that the cGAS/STING pathway contributes to generating Th2 cells and inhibiting Th1 cell expansion.…”

Section: Discussionmentioning

confidence: 99%

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

et al. 2019

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Graphical Abstract Highlights d Silica impairs host control of M. tuberculosis infection via a type 2 immune response d Extracellular DNA potentiates silica-induced exacerbation of M. tuberculosis infection d Silica primes STING activation, potentiating the response to M. tuberculosis DNA d Both host and M. tuberculosis DNA trigger cGAS/STING/ IFNI-mediated type 2 immunity SUMMARY Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silicadriven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

et al. 2019

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“…Mice deficient in DNase I or DNase II develop a lupus like disease (26, 27) and animals or humans lacking TREX1 (DNase III) acquire a number of inflammatory diseases (28, 29). Additionally, others have shown that naked, isolated, host DNA can, if co-injected with antigen, act as an adjuvant on its own (2, 30, 31). …”

Section: Discussionmentioning

confidence: 99%

Contamination of DNase Preparations Confounds Analysis of the Role of DNA in Alum-Adjuvanted Vaccines

Noges

White

Cambier

et al. 2016

The Journal of Immunology

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Aluminum salt (alum) adjuvants have been used for many years as adjuvants for human vaccines because they are safe and effective. In spite of its widespread use, the means by which alum acts as an adjuvant remains poorly understood. Recently, it was shown that injected alum is rapidly coated with host chromatin within mice. Experiments suggested that the host DNA in the coating chromatin contributed to alum’s adjuvant activity. Some of the experiments used commercially purchased DNase and showed that co-injection of these DNase preparations with alum and antigen reduced the host’s immune response to the vaccine. Here we report that some commercial DNase preparations are contaminated with proteases. These proteases are responsible for most of the ability of DNase preparations to inhibit alum’s adjuvant activity. Nevertheless, DNase somewhat reduces responses to some antigens with alum. The effect of DNase is independent of its ability to cleave DNA, suggesting that alum improves CD4 responses to antigen via a pathway other than host DNA sensing.

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“…Similarly, a Sendai virus-derived 546-nucleotide ligand of RIG-I enhanced immunogenicity of influenza DNA vaccine [70]. TLRs, RIG-I-like receptor (RLRs), inflammasome and STING-dependent cytosolic DNA sensor ligands can all initiate Th2 cell differentiation [71]. Ligands of the cytosolic DNA sensor DAI have also been shown to be efficient molecular adjuvant for DNA cancer vaccines [72].…”

Section: Ligands Of Pattern Recognition Receptorsmentioning

confidence: 99%

“…eRNA41H, shown to enhance DNA vaccine action [69]. STING ligand can initiate Th2 cell differentiation in mouse model [71]. Ligands to dsDNA sensor, DA1, shown to be efficient adjuvants for cancer DNA vaccines [72].…”

Section: Removal Of Bacterial Elementmentioning

confidence: 99%

Molecular mechanisms for enhanced DNA vaccine immunogenicity

Petrovsky

2015

Expert Review of Vaccines

252

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Summary In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.

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Nucleic acid sensing by T cells initiates Th2 cell differentiation

Cited by 38 publications

References 52 publications

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity

Contamination of DNase Preparations Confounds Analysis of the Role of DNA in Alum-Adjuvanted Vaccines

Molecular mechanisms for enhanced DNA vaccine immunogenicity

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