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TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice

Significance Toll-like receptors (TLRs) that sense microbial or endogenous DNA and RNA have been well implicated in systemic lupus erythematosus (SLE), a multisystem disease characterized by an autoimmune response to nuclear antigens. In mice, both TLR8 and TLR9 control TLR7-mediated lupus, but it is unknown if they have an additive effect in controlling TLR7. We demonstrate that double TLR8/9-deficient mice have increased abnormalities characteristic of SLE and that both TLR8 and TLR9 keep under control TLR7-mediated lupus, but they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells. These TLR interactions have to be taken into account when novel therapeutic approaches are developed that target the blocking of TLRs. Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9−/−) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8−/− or TLR9−/− mice. On the cellular level, TLR8−/− and TLR8/9−/− dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9−/− cells responded normally. Moreover, B cells from TLR9−/− and TLR8/9−/− mice were hyperesponsive to R848, but TLR8−/− B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells.