Background/Purpose 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. We hypothesize that one mechanism of suppression is an IFNγ inducible immunosuppressive on the tissue parenchyma. Previously we and others have shown that PD-L1 is upregulated on the parenchyma of lupus nephritis patients and lupus-prone mice. KITs have high expression of PD1 when compared to lymphoid T cells from the same mouse. Furthermore, IFNγ is the major inducer of PD-L1.

Therefore, we postulated that IFNγ induces a protective program mediated by PD-L1 which results in suppresses immune destruction of the kidney in lupus nephritis.

MRL Fas^lpr mice develop autoantibodies, proteinuria, dermatitis, and glomerulonephritis. To determine if 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. If our hypothesis is correct, then both IFNγR^-/- and PD-L1^-/- recipients would have more severe disease than their WT counterparts. Chimerization occurred at 4-6 weeks of age, female and male mice were analyzed for disease pathology at 4-6 months post-chimerization depending on genetic background. Analysis included proteinuria, renal histology for both interstitial and glomerular disease, dermatitis, autoantibody production, and immune cell activation. Additional analysis focused specifically on T cell phenotypes.

Results As hypothesized, the IFNγR^-/- MRL.Fas^lpr recipient mice exhibited more severe and rapid disease onset than WT recipient controls. 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. However, there was no appreciable difference between PD-L1^-/- MRL.Fas^lpr recipient compared to controls, they had no increase in mortality nor significant difference is nephritis status. When examining infiltrates, KITs isolated from IFNγR^-/- recipients exhibited increased expression of Tim3 and PD-1. Similar to the disease endpoints, these T cells changes were not noted in the PD-L1^-/- MRL.Fas^lpr recipient mice .

Conclusion These experiments suggest that parenchymal IFNγR signaling results in upregulation of protective mechanisms which reduce kidney disease and alter T cell phenotypes. While we hypothesized that this would be mediated through IFNγ induced PD-L1 the latter hypothesis does not appear to be supported. This data contrasts with global IFNγR^-/- which ameliorated kidney disease and global PD-L1 deficiency which led to increased mortality in MRL.Fas^lpr mice. Overall, 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. Furthermore, this work shows that this IFNγ response is independent of PD-L1 signaling. In all, these findings should be considered when devising novel targeted therapies.