2′-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity
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.
Authors
- Ben Corry (ORCID: https://orcid.org/0000-0002-6324-442X)
- Wan L. Lam (ORCID: https://orcid.org/0000-0002-0945-0644)
- Toshiyuki Shimizu (ORCID: https://orcid.org/0000-0002-0547-8922)
- Julia I. Ellyard
- Refaya Rezwan (ORCID: https://orcid.org/0000-0002-2859-2461)
- Zhikuan Zhang
- Liza Cubeddu
- Daniel S. Wenholz (ORCID: https://orcid.org/0000-0002-5526-4359)
- Mark A. Behlke (ORCID: https://orcid.org/0000-0002-4218-857X)
- Michael Paul Gantier (ORCID: https://orcid.org/0000-0003-3740-698X)
- Ruitao Jin (ORCID: https://orcid.org/0000-0002-7934-250X)
- Arwaf Alharbi (ORCID: https://orcid.org/0000-0003-3694-1067)
- Hani Hosseini Far
- Lorna Wilkinson‐White (ORCID: https://orcid.org/0000-0002-2385-9358)
- Umeharu Ohto (ORCID: https://orcid.org/0000-0002-4422-4044)
- Marina R. Alexander (ORCID: https://orcid.org/0000-0003-0745-7903)
- Olivier Laczka (ORCID: https://orcid.org/0000-0003-0966-9897)
- Sunil Sapkota (ORCID: https://orcid.org/0000-0001-7901-9879)
- Josiah Bones (ORCID: https://orcid.org/0000-0001-5419-9914)
- Roland Gamsjaeger (ORCID: https://orcid.org/0000-0003-1095-2569)
- Sitong He (ORCID: https://orcid.org/0000-0001-9297-2859)
- Alexandra L. McAllan
- Erandi Rupasinghe
- Mary Speir
- Juliane Paul
- Claudia A. Nold-Petry
- W. Samantha N. Jayasekara
- Le Ying
- Cameron R. Stewart
- Rui Gao
- Rasan M. Sathiqu
- Dingyi Yu
- Carola G. Vinuesa
Institutions
- Australian National University (AU)
- The University of Sydney (AU)
- Australian Centre for Disease Preparedness (AU)
- Taif University (SA)
- The Francis Crick Institute (GB)
- Hudson Institute of Medical Research (AU)
- New South Wales Institute of Psychiatry (AU)
- CSIRO Health and Biosecurity (AU)
- Panaquatic (AU)
- Monash University (AU)
- Western Sydney University (AU)
- Integrated DNA Technologies (United States) (US)
- The University of Tokyo (JP)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-02-10
- DOI
- https://doi.org/10.1038/s41590-026-02429-2
- Citations
- 2
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 48.87