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The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4 + T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim-1 in experimental T-cell–mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4 + cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3 + cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis.

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-γ 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.