IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN
Copyright © 2018 by the American Society of Nephrology..
Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum-induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.Results Compared with controls, mice with IL-10Ra-/- Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra-/- Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra-/- Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra-/- T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Journal of the American Society of Nephrology : JASN - 29(2018), 7 vom: 02. Juli, Seite 1825-1837 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Diefenhardt, Paul [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.09.2019 Date Revised 06.09.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1681/ASN.2017091044 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM285118447 |
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| 245 | 1 | 0 | |a IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Revised 06.09.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 by the American Society of Nephrology. | ||
| 520 | |a Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum-induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.Results Compared with controls, mice with IL-10Ra-/- Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra-/- Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra-/- Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra-/- T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a IL-10R | |
| 650 | 4 | |a IL-17 | |
| 650 | 4 | |a Interleukin 10 | |
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| 650 | 4 | |a glomerulonephritis | |
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| 650 | 7 | |a Interleukin-10 Receptor alpha Subunit |2 NLM | |
| 650 | 7 | |a Receptors, CCR6 |2 NLM | |
| 650 | 7 | |a Interleukin-10 |2 NLM | |
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| 700 | 1 | |a Nosko, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Kluger, Malte A |e verfasserin |4 aut | |
| 700 | 1 | |a Richter, Johannes V |e verfasserin |4 aut | |
| 700 | 1 | |a Wegscheid, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Yasushi |e verfasserin |4 aut | |
| 700 | 1 | |a Tiegs, Gisa |e verfasserin |4 aut | |
| 700 | 1 | |a Huber, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Flavell, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a Stahl, Rolf A K |e verfasserin |4 aut | |
| 700 | 1 | |a Steinmetz, Oliver M |e verfasserin |4 aut | |
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