Background Lupus nephritis is the most common life-threatening end-organ complication of SLE. Interstitial infiltrates, specifically T cells, are major predictors of disease outcomes. We recently determined that kidney-infiltrating T cells (KITs) are suppressed after kidney infiltration and exhibit an exhausted phenotype. Notably, the kidneys of nephritic lupus-prone (MRL.Fas lpr) mice upregulate PD-L1, which we hypothesize is one mechanism inducing KIT suppression. IFNγ is the major inducer of PD-L1 and given the known role of IFNγ in lupus nephritis, we postulated that IFNγ induces a protective program in the kidneys of lupus-prone mice, in direct contrast to the proinflammatory role of IFNγ in the hematopoietic compartment.
Methods MRL. Fas lpr mice develop autoantibodies, proteinuria, dermatitis, and glomerulonephritis. Others have previously shown that global IFNγ receptor deficiency (IFNγR-/-) ameliorates disease in this mouse model. To determine if IFNγ signaling on parenchymal cells regulates disease, we generated bone marrow chimeras by transferring congenically labeled WT immune cells into either wild-type (WT) or IFNγR-/- MRL.Fas lpr recipients. If our hypothesis is correct, then the IFNγR-/- recipients would have more severe disease than their WT counterparts. Chimerization occurred at 4-6 weeks of age and female and male mice were analyzed for disease pathology at 23 and 27 weeks post-chimerization respectively. Analysis included proteinuria, renal histology for both interstitial and glomerular disease, dermatitis, autoantibody production, and immune cell activation. Survival analysis was performed on female mice. Additional analysis focused specifically on T cell phenotypes.
Results IFNγR-/- MRL.Fas lpr recipient mice exhibited more severe and rapid disease onset than WT recipient controls. While proteinuria was not different between the two groups, the IFNγR-/- recipients had more severe glomerulonephritis (p< 0.005) and interstitial disease (p< 0.001). Consistent with these findings, IFNγR-/- recipients had reduced survival (p< 0.05). As expected, IFNγR deficiency resulted in reduced PD-L1 expression. When examining infiltrates, KITs isolated from IFNγR-/- recipients exhibited increased expression of Tim3 and PD-1.
Conclusions These experiments suggest that parenchymal IFNγR signaling results in upregulation of protective mechanisms which reduce kidney disease and alter T cell phenotypes. This contrasts with global IFNγR-/- which ameliorated kidney disease. Overall, this finding argues that suppression of IFNγ, and possible other inflammatory mediators, may have differential effects on specific cell lineages and that global suppression of IFNγR may have both positive and negative effects on disease pathogenesis. This will need to be considered when devising targeted therapies.
Acknowledgments This work was supported by the Lupus Research Alliance (Novel Research Grant), NIAID (R01 AI137132), and J.T was supported by NIAMS 5K08AR075056.
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