ArticleNature immunology2026
2'-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity.
Article in Nature immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed.
- Mosaic TLR8 gain-of-function in an elderly female treated with JAK inhibitor and adjunctive therapy.Journal of human immunity · 2026Article
- The SLC15A4-TASL complex is essential for lupus development in mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Sub-stoichiometric 5-methoxyuridine modification enables tunable immune evasion and protein expression from synthetic mRNAs.Molecular therapy. Nucleic acids · 2026Article
- TLR7 in systemic lupus erythematosus: genetics and emerging therapies.Nature reviews. Rheumatology · 2026Review
- Article
- Phosphorothioate antisense oligonucleotide induced innate immune activation is attenuated by tryptophan oxidation products.Nucleic acids research · 2026Article
- An inhibitory RNA checkpoint in TLR7 and TLR8.Nature immunology · 2026Article
- The plasmacytoid dendritic cell paradox in cancer: impaired type I interferon responses in a nucleic acid-rich tumor microenvironment.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
33 authors.
Funding
Abstract
Recognition of RNA fragments by Toll-like receptor 7 (TLR7) and TLR8 helps to initiate the innate immune response against pathogens. An outstanding question is why RNA fragments generated during clearance of apoptotic cells fail to activate TLR7 and TLR8 signaling. Here we show that select 2'-O-methyl (2'-OMe) guanosine RNA fragments, including those derived from host RNAs, function as potent TLR7 and TLR8 antagonists and reduce TLR7 sensing in vivo. Mechanistically, these fragments bind to an antagonistic site on these proteins via their 5'-end 2'-OMe guanosine. These findings indicate that host RNAs evade detection because abundant ribosomal 2'-OMe-modified fragments naturally antagonize TLR7 and TLR8. Crucially, rare TLR7 and TLR8 mutations at this antagonist binding site decrease inhibition by 2'-OMe guanosine RNA fragments, leading to autoimmunity in patients. Collectively, this work redefines TLR7 and TLR8 sensing by introducing 2'-OMe guanosine as a natural immune checkpoint for their activation.
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