2’-O-Methyl-guanosine 3-base RNA fragments mediate essential natural TLR7/8 antagonism

Recognition of RNA fragments by Toll-like receptors (TLR) 7 and 8 is a key contributor to the initiation of a protective innate immune response against pathogens. A long-standing enigma is how degradation products of host RNAs, generated by the daily phagocytic clearance of billions of apoptotic cells, fail to activate TLR7 and TLR8 signalling ¹ . Here, we report that select 2’-O-methyl (2’-Ome) guanosine RNA fragments as short as 3 bases, including those derived from host-RNAs, are potent TLR7 and TLR8 antagonists that reduce TLR7 sensing in vivo . Mechanistically, antagonistic fragments are directed towards a distinct binding site on these proteins by 5’-end 2’-Ome guanosine. Our results indicate that host-RNAs evade detection by TLR7/8 due to a pool of abundant host ribosomal 2’-Ome-modified RNA fragments that naturally antagonize TLR7 and TLR8 sensing to avoid auto-immunity. Crucially, rare TLR7 and TLR8 mutations located at this antagonistic site decrease the inhibitory activity of 2’-Ome guanosine RNA fragments and lead to auto-immunity in patients. Our findings also establish that select chemically synthesised 3-base oligonucleotides can harness the protective anti-inflammatory activity of this natural immune checkpoint for therapeutic targeting of TLR7-driven diseases.