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 3

TLR779 protects from lupus disease.

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TLR779 protects from lupus disease. 16–18-week-old Tlr7+/+, Tlr779/779 o...
16–18-week-old Tlr7+/+, Tlr779/779 or Tlr7–/– (all Tlr9–/–) MRL/lpr mice were assessed for disease endpoints. Disease endpoints were also assessed in age-matched WT Tlr7+/+ and Tlr9+/+ MRL/lpr mice as a reference but were not included in the statistical analysis (B–E). (A) Schematic of the different mouse genotypes that are compared. The groups were labeled Tlr7+/+, Tlr779/779 or Tlr7–/– if both males and females were included. (B and C) Spleen and lymph node weights were measured in mice of the indicated sex and genotypes. (D) Kidney pathology was assessed in mice of the indicated sex and genotypes. For B–D, reference group female n = 12, male n = 11; experimental group female Tlr7+/+n = 19, Tlr779/779 n = 21, Tlr7–/– n = 25; male Tlr7+/Yn = 20, Tlr779/Y n = 24, Tlr7–/Y n = 14. (E) Quantification of anti-RNA (reference group n = 9; experimental group Tlr7+/+n = 6, Tlr779/779 n = 13, all females) and anti-Smith autoantibodies (reference group n = 18; experimental group Tlr7+/+n = 16, Tlr779/779 n = 19, males and females). (F–H) Splenic B and T cell subsets were assessed by flow-cytometry in MRL/lpr mice of the indicated genotypes. (F) Percent of CD19+ cells among live splenocytes, and CD11b+ CD11c+ ABCs among live B cells (CD19+: Tlr7+/+n = 14, Tlr779/779 n = 25, Tlr7–/– n = 24; ABC: Tlr7+/+n = 12, Tlr779/779 n = 17, Tlr7–/– n = 24). (G) Percent of TCR–CD44hiCD138+ plasmablasts among live splenocytes in mice of the indicated genotypes (Tlr7+/+n = 9, Tlr779/779 n = 25, Tlr7–/– n = 24). (H) Percent of naive (CD62Lhi CD44lo), activated (CD62Lhi CD44hi), and memory (CD62Llo CD44hi) T cells among live TCR+ CD4+ splenocytes (Tlr7+/+n = 14, Tlr779/779 n = 25, Tlr7–/– n = 24). 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, using a 1-way ANOVA with Tukey’s multiple comparisons test for all panels except E; Mann-Whitney test for panel E.