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-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.
Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, Monash University, Victoria, Australia.
Joshua D
JD
Ooi
Sarah L
SL
Snelgrove
Daniel R
DR
Engel
Katharina
K
Hochheiser
Isis
I
Ludwig-Portugall
Yuji
Y
Nozaki
Kim M
KM
O'Sullivan
Michael J
MJ
Hickey
Stephen R
SR
Holdsworth
Christian
C
Kurts
A Richard
AR
Kitching
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology*; D005921:Glomerulonephritis / Q000276:immunology / Q000517:prevention & control*; D007108:Immune Tolerance; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013997:Time Factors
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse