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

Joshua Ooi, Sarah Snelgrove, Daniel Engel, Katharina Hochheiser, Isis Ludwig-Portugall, Yuji Nozaki, Kim O'Sullivan, Michael Hickey, Stephen Holdsworth, Christian Kurts, Arthur Kitching

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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-I? 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.
Original languageEnglish
Pages (from-to)977 - 986
Number of pages10
JournalKidney International
Volume79
Issue number9
DOIs
Publication statusPublished - 2011

Cite this

Ooi, Joshua ; Snelgrove, Sarah ; Engel, Daniel ; Hochheiser, Katharina ; Ludwig-Portugall, Isis ; Nozaki, Yuji ; O'Sullivan, Kim ; Hickey, Michael ; Holdsworth, Stephen ; Kurts, Christian ; Kitching, Arthur. / Endogenous foxp3{+} T-regulatory cells suppress anti-glomerular basement membrane nephritis. In: Kidney International. 2011 ; Vol. 79, No. 9. pp. 977 - 986.
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title = "Endogenous foxp3{+} T-regulatory cells suppress anti-glomerular basement membrane nephritis",
abstract = "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-I? 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.",
author = "Joshua Ooi and Sarah Snelgrove and Daniel Engel and Katharina Hochheiser and Isis Ludwig-Portugall and Yuji Nozaki and Kim O'Sullivan and Michael Hickey and Stephen Holdsworth and Christian Kurts and Arthur Kitching",
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Endogenous foxp3{+} T-regulatory cells suppress anti-glomerular basement membrane nephritis. / Ooi, Joshua; Snelgrove, Sarah; Engel, Daniel; Hochheiser, Katharina; Ludwig-Portugall, Isis; Nozaki, Yuji; O'Sullivan, Kim; Hickey, Michael; Holdsworth, Stephen; Kurts, Christian; Kitching, Arthur.

In: Kidney International, Vol. 79, No. 9, 2011, p. 977 - 986.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Endogenous foxp3{+} T-regulatory cells suppress anti-glomerular basement membrane nephritis

AU - Ooi, Joshua

AU - Snelgrove, Sarah

AU - Engel, Daniel

AU - Hochheiser, Katharina

AU - Ludwig-Portugall, Isis

AU - Nozaki, Yuji

AU - O'Sullivan, Kim

AU - Hickey, Michael

AU - Holdsworth, Stephen

AU - Kurts, Christian

AU - Kitching, Arthur

PY - 2011

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N2 - 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-I? 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.

AB - 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-I? 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.

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DO - 10.1038/ki.2010.541

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JO - Kidney International

JF - Kidney International

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