Impact of SLC15A4, TASL and TASL2(Gm6377) deficiency on endolysosomal TLR7 and TLR9 responses. Impact of SLC15A4, TASL and TASL2(Gm6377) deficiency on endolysosomal TLR7 and TLR9 responses

Nucleic acid sensing by endolysosomal TLR7-9 results in the induction of antiviral and proinflammatory transcriptional responses. We recently identified TASL as the innate immune adaptor mediating TLR7-9-induced IRF5 activation via the interaction with SLC15A4, but its relevance in primary murine cells remained unexplored. Here we assessed the impact of deficiency in TASL and/or its previously uncharacterized paralogue Gm6377, named here TASL2, on endolysosomal TLR responses in primary bone-marrow-derived pDCs and splenic B cells. Double knockout TASLxTASL2 (TASLDKO) phenocopied the strong impairement observed in cells from SLC15A4-deficient feeble mice, while single TASL or TASL2 deficiency showed partial effect. Altogether, this study demonstrates that the SLC15A4-TASL/TASL2 complex play a critical role for TLR7-9-driven inflammatory responses. Overall design: To investigate the function of SLC15A4-TASL complex in TLR7-9 induced signaling, we compared transcriptional profile of 5 different genotypes (WT, TASLKO, TASL2KO, TASLDKO, feeble - SLC15A4 deficient) in steady state and upon activation with TLR7 or TLR9 agonists. For this, bone marrow derived plasmacytoid dendritic cells (BM-pDC) and primary splenic B cells were used in 3-4 biological replicates for each genotype.