Abstract Text: 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. PD-L1 is upregulated on the parenchyma of lupus nephritis patients and lupus-prone mice. Therefore, we postulated that IFNγ induces a protective program mediated by PD-L1 which results in suppressed immune mediated destruction of the kidney in lupus nephritis.
Methods To determine whether PD-L1 and 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 or PD-L1-/- MRL.Fas/lpr recipients. Additionally, we have created similar IFNγR-/- recipient chimeras using a second lupus prone strain, the FcγR2b-/-.yaa model.
Results/Discussion As hypothesized, the IFNγR-/- MRL.Fas/lpr recipient mice exhibited more severe and rapid disease onset than WT recipient controls. The IFNγR-/- recipients had significantly increased glomerulonephritis and interstitial disease. Consistent with these findings, IFNγR-/- recipients had reduced survival in both the MRL and FcγR2b-/-.yaa nephritis models. Interestingly, this IFNγR mediated regulation of disease occurred independently of PD-L1 as similar findings were not observed in PD-L1 deficient recipients.
These experiments suggest that parenchymal IFNγR signaling results in upregulation of protective mechanisms which reduces kidney disease and alters T cell phenotypes. This data supports the hypothesis that IFNγ, and possible other inflammatory mediators, may have differential effects varying cell lineages. In all, these findings should be considered when devising novel targeted therapies.
