Endogenous foxp3+ T-regulatory cells suppress anti-glomerular basement membrane nephritis.

Foxp3+ T-regulatory cells (Tregs) may suppress pathogenic inflammation; however, although transferred Tregs lessen glomerulonephritis in mice, the role of endogenous foxp3 cells is not known. To study this, we characterized endogenous foxp3 cells in accelerated anti-glomerular basement membrane (GBM) nephritis by using foxp3 GFP reporter mice to track their responses in early and established disease. Further, diphtheria toxin was used to ablate foxp3 Tregs in foxp3 DTR mice after establishing an immune response. In this model, mice were immunized with sheep globulin in adjuvant, and sheep anti-mouse GBM globulin was injected after 4 days to initiate progressive histological and functional injury. Intrarenal leukocytic infiltrates were increased by day 3 but intrarenal foxp3 Tregs, present in interstitial and periglomerular areas, were only increased at day 7. Ablation of foxp3 Tregs after injection of anti-GBM globulin increased renal injury and systemic T-cell responses, including increased interferon-gamma and interleukin-17A (IL-17A) production, but no change in antibody titers. Compared with foxp3 Tregs isolated from naive mice, those from immunized mice produced more IL-10 and more effectively regulated CD4 foxp3 responder T cells. Thus, endogenous foxp3 Tregs infiltrate the kidney in glomerulonephritis, and deleting foxp3 cells after the induction of immune responses upregulated T-cell reactions and enhanced disease. Hence, endogenous foxp3 cells have increased suppressive capacity after immune stimuli. © 2011 International Society of Nephrology.