Divergent TIR signaling domains in TLR7 and TLR9 control opposing effects on systemic autoimmunity
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
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Research Article Autoimmunity Immunology

Divergent TIR signaling domains in TLR7 and TLR9 control opposing effects on systemic autoimmunity

Abstract

Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates the disease while TLR9 protects from it How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous Tlr7 locus and the TLR7 TIR domain into the endogenous Tlr9 locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL/lpr mice carrying Tlr779 had greatly ameliorated disease, while MRL/lpr mice carrying Tlr997 had markedly exacerbated disease compared with respective TlrWT mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding “TLR paradox”.

Authors

Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik

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Figure 7

TLR997 exacerbates lupus disease.

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TLR997 exacerbates lupus disease. 18–21-week-old Tlr9+/+, Tlr9+/– or Tlr...
18–21-week-old Tlr9+/+, Tlr9+/– or Tlr997/997 (referred to as Tlr997) (all Tlr7–/–) MRL/lpr mice were assessed for disease endpoints. Disease endpoints were also assessed in 18–20-week-old WT Tlr7+/+ and Tlr9+/+ MRL/lpr mice as a reference but were not included in the statistical analysis (B and C). (A) Schematic of the different mouse genotypes that are compared. (B) Spleen weights were measured in mice of the indicated gender and genotypes. (C) Kidney pathology was assessed in mice of the indicated gender and genotypes. (For B and C, female Tlr9+/+n = 17, Tlr9+/– n = 28, Tlr997 n = 22, Tlr9+/+ Tlr7+/+ n = 8; male Tlr9+/+n = 16, Tlr9+/– n = 24, Tlr997 n = 11, Tlr9+/+ Tlr7+/Y n = 2 or 3) (D) Splenic B cell subsets were assessed by flow cytometry in mice of the indicated genotypes. Percent of CD19+ cells among live splenocytes, and percent of CD23lo CD21hi MZ, CD11b+ CD11c+ ABCs and CD11b+ cells among live B cells (Tlr9+/+ n = 26, Tlr9+/– n = 36, Tlr997 n = 25). For all panels, data points indicate individual mice and bars indicate the mean ± SEM. For statistics, *P < 0.05, **P < 0.01, ****P < 0.001, ****P < 0.0001, 1-way ANOVA with Tukey’s multiple comparisons test.