A Novel Role for IL-6 Receptor Classic Signaling : Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity
Copyright © 2019 by the American Society of Nephrology..
BACKGROUND: New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.
METHODS: To learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.
RESULTS: Lack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra-/- Tregs resulted in severe aggravation of GN in mice.
CONCLUSIONS: Our data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell-intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific.
| Errataetall: |
CommentIn: J Am Soc Nephrol. 2019 Aug;30(8):1341-1344. - PMID 31366693 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Journal of the American Society of Nephrology : JASN - 30(2019), 8 vom: 11. Aug., Seite 1439-1453 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hagenstein, Julia [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.04.2020 Date Revised 01.08.2020 published: Print-Electronic CommentIn: J Am Soc Nephrol. 2019 Aug;30(8):1341-1344. - PMID 31366693 Citation Status MEDLINE |
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| doi: |
10.1681/ASN.2019020118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM299247112 |
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| 100 | 1 | |a Hagenstein, Julia |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Novel Role for IL-6 Receptor Classic Signaling |b Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 27.04.2020 | ||
| 500 | |a Date Revised 01.08.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Am Soc Nephrol. 2019 Aug;30(8):1341-1344. - PMID 31366693 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 by the American Society of Nephrology. | ||
| 520 | |a BACKGROUND: New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown | ||
| 520 | |a METHODS: To learn more about the complex role of CD4+ T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations | ||
| 520 | |a RESULTS: Lack of IL-6Ra signaling in mouse CD4+ T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced RORγt+Foxp3+ double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra-/- Tregs resulted in severe aggravation of GN in mice | ||
| 520 | |a CONCLUSIONS: Our data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell-intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt+ biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a chemokine receptor | |
| 650 | 4 | |a glomerulonephritis | |
| 650 | 4 | |a immunology and pathology | |
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| 650 | 7 | |a Il6ra protein, mouse |2 NLM | |
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| 650 | 7 | |a Interleukin-6 Receptor alpha Subunit |2 NLM | |
| 650 | 7 | |a Nuclear Receptor Subfamily 1, Group F, Member 3 |2 NLM | |
| 650 | 7 | |a Receptors, Interleukin-6 |2 NLM | |
| 650 | 7 | |a Rorc protein, mouse |2 NLM | |
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| 700 | 1 | |a Nosko, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Warkotsch, Matthias T |e verfasserin |4 aut | |
| 700 | 1 | |a Richter, Johannes V |e verfasserin |4 aut | |
| 700 | 1 | |a Ramcke, Torben |e verfasserin |4 aut | |
| 700 | 1 | |a Herrnstadt, Georg R |e verfasserin |4 aut | |
| 700 | 1 | |a Scheller, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Isabell |e verfasserin |4 aut | |
| 700 | 1 | |a Mittrücker, Hans-Willi |e verfasserin |4 aut | |
| 700 | 1 | |a Kluger, Malte A |e verfasserin |4 aut | |
| 700 | 1 | |a Steinmetz, Oliver M |e verfasserin |4 aut | |
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