Science Bite (3 minute oral presentation with PPT in live session and poster) - Students, ECRs and EMCRs only 16th Lorne Infection and Immunity 2026

The unusual TLR family member RP105 is the dominant TLR2 co-receptor for mycobacteria-induced macrophage IL-12p40 production (132572)

Leslie C. Domínguez Cadena 1 , Thomas E. Schultz 1 , Carmen D. Mathmann 1 , Meg L Donovan 1 , Ashleigh Gordon 1 , Isis Taylor 1 , Alun Jones 2 , Dorothy Loo 3 , Janelle Hancock 3 , Alina Vitak 1 , Matt J. Sweet 2 , Antje Blumenthal 1
  1. Frazer Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  3. Translational Research Institute, Brisbane, Queensland, Australia

The IL-12p40 cytokine subunit is critical for host defence against mycobacteria. Macrophages are major host cells for mycobacteria and a key cellular source of IL-12p40. Toll-like receptor 2 (TLR2) is a central driver of mycobacteria-induced IL-12p40 production. TLR2 heterodimerises with TLR1 or TLR6 to facilitate cellular activation, and both co-receptors contribute to host recognition of mycobacteria. Which TLR2 co-receptor interactions are required for mycobacteria-induced macrophage IL-12p40 production is unknown. Using primary murine macrophages, we confirmed requirement of TLR2 for macrophage IL-12p40 responses to Mycobacterium bovis BCG (BCG), the current tuberculosis vaccine. Contrary to expectations, neither TLR1 nor TLR6 were necessary for BCG-induced macrophage IL-12p40 responses. Instead, the TLR family member Radioprotective 105 (RP105) was required for BCG-induced IL-12p40 production in a manner dependent on TLR2. RP105 lacks the TLR intracellular Toll/IL-1 receptor domain essential for TLR signalling, which is consistent with lack of RP105 contributions to canonical TLR2 signalling. How RP105 contributes to mycobacteria-induced macrophage activation is unknown. RP105 contains a short cytoplasmic tail with evolutionary conserved amino acid residues of unknown function. Employing targeted mutagenesis and retroviral reconstitution of Rp105-deficient primary macrophages, we show that conserved amino acids in the RP105 cytoplasmic tail were essential for BCG-induced macrophage IL-12p40 production in a manner dependent on TLR2. Furthermore, biochemical analyses combined with high-resolution microscopy revealed that the RP105 cytoplasmic tail regulates RP105 subcellular distribution in macrophages and serves as a recruitment platform for intracellular trafficking, signalling and scaffolding machinery in BCG-infected macrophages. These findings uncovered, for the first time, a functional role for the RP105 cytoplasmic tail in the host recognition of mycobacteria. Collectively, our data highlight a key role for RP105 as the dominant TLR2 co-receptor in the recognition of mycobacteria and provide the basis for delineating unconventional TLR signalling events that orchestrate key host responses to mycobacterial infection.