Murine Toll-like receptor 8 is a functional sensor of nucleic acid fragments

Murine TLR8 is an active nucleic acid sensor that responds to TL8-506 and 2',3'-cGMP, with signalling boosted by cooperative binding of nucleic acid fragments at a secondary site.

• Why it matters: Murine TLR8 has been considered unable to detect nucleic acids, leaving a gap in how mouse endosomal nucleic acid sensing works compared with the well-established human TLR8.
• What they did: The study tested mTLR8 signalling to TL8-506 and 2',3'-cGMP and found potentiation by cooperative fragment binding at a secondary ligand-binding site; it also used Tlr7-deficient mice expressing mTlr8 under the Tlr7 promoter.
• The result: In splenocytes from these mice, mTLR8 partially restored TLR7-dependent tonic transcriptional programs, and a human-mouse TLR8 knock-in showed the mTLR8 ectodomain is intrinsically less sensitive, supporting combinatorial sensing of nucleic acid degradation products.

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