Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Pandey, Surya Prakash; Kawai, Taro; Akira, Shizuo

doi:10.1101/cshperspect.a016246

Cited by 315 publications

(341 citation statements)

References 139 publications

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“…While probing the roles of GARP in immunity, we discovered that GARP is significantly upregulated on peripheral B cells in systemic autoimmune diseases and GARP expression is the basis for TGF-β presence on the cell surface. Importantly, we found that multiple MyD88-dependent TLR ligands (70), including ligands for TLR4, TLR7, and TLR9, drive surface GARP expression on normal B cells, raising an intriguing possibility that the GARP-TGF-β axis on activated B cells is a checkpoint for maintaining B cell peripheral tolerance. We addressed this hypothesis critically using multiple genetic models, including GARP conditional KO and OE systems.…”

Section: Discussionmentioning

confidence: 95%

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B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

Wallace¹,

Wu²,

Salem³

et al. 2018

JCI Insight

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Section: Discussionmentioning

confidence: 95%

“…NF-κB is the common downstream molecule of multiple MyD88-dependent TLR signaling cascades (70). It is possible that TLR signaling induces GARP expression via NF-κB, as suggested by the presence of a putative NF-κB-binding site in the promoter region of Lrrc32 (82).…”

Section: Discussionmentioning

confidence: 99%

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

Wallace¹,

Wu²,

Salem³

et al. 2018

JCI Insight

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“…Viral vectors, even if not replicative, mimic an acute pathogenic viral infection, sending a compendium of alarm signals that call for a CTL-mediated immune response (25). We hypothesize that mimicking viral infection of the tumor should trigger or sustain the proper type of cytotoxic inflammation in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Virotherapy with a Semliki Forest Virus–Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

Quetglas

Labiano

Aznar

et al. 2015

Cancer Immunology Research

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Virotherapy and checkpoint inhibitors can be combined for the treatment of cancer with complementarity and potential for synergistic effects. We have developed a cytolytic but nonreplicative viral vector system based on Semliki Forest virus that encodes IL12 (SFV-IL12). Following direct intratumoral injection, infected cells release transgenic IL12, die, and elicit an inflammatory response triggered by both abundantly copied viral RNA and IL12. In difficult-to-treat mouse cancer models, such as those derived from MC38 and bilateral B16-OVA, SFV-IL12 synergized with an anti-PD-1 monoclonal antibody (mAb) to induce tumor regression and prolong survival. Similar synergistic effects were attained upon PD-L1 blockade. Combined SFV-IL12 þ anti-PD-1 mAb treatment only marginally increased the elicited cytotoxic T-lymphocyte response over SFV-IL12 as a single agent, at least when measured by in vivo killing assays. In contrast, we observed that SFV-IL12 treatment induced expression of PD-L1 on tumor cells in an IFNgdependent fashion. PD-L1-mediated adaptive resistance thereby provides a mechanistic explanation of the observed synergistic effects achieved by the SFV-IL12 þ anti-PD-1 mAb combination.

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“…In vertebrate animals, the immune system deploys sensors of DNA and RNA to detect microbial infections (1)(2)(3). In addition to a subset of Tolllike receptors that detect microbial nucleic acids in the lumen of endosomes, cytosolic nucleic acid sensors also play crucial roles in detecting pathogens, especially those that have successfully breached the membrane barriers and replicated in the interior of a cell.…”

Section: Trex1mentioning

confidence: 99%

Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases

Gao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

567

508

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TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans. Trex1−/− mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation of cGas in Trex1−/− mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescued the phenotypes of Trex1−/− mice. Similarly, deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of the DNaseII−/− mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases in Trex1−/− and DNaseII−/− mice and suggest that inhibition of cGAS may lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.

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Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid Sensors

Cited by 315 publications

References 139 publications

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

Virotherapy with a Semliki Forest Virus–Based Vector Encoding IL12 Synergizes with PD-1/PD-L1 Blockade

Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases

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