The CCR6/CCL20 axis expands RORγt+ Tregs to protect from glomerulonephritis
Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.
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CommentIn: Kidney Int. 2023 Jul;104(1):28-31. - PMID 37349057 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:104 |
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| Enthalten in: |
Kidney international - 104(2023), 1 vom: 15. Juli, Seite 74-89 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Herrnstadt, Georg R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.06.2023 Date Revised 22.11.2023 published: Print-Electronic CommentIn: Kidney Int. 2023 Jul;104(1):28-31. - PMID 37349057 Citation Status MEDLINE |
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| doi: |
10.1016/j.kint.2023.02.027 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354304046 |
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| 100 | 1 | |a Herrnstadt, Georg R |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The CCR6/CCL20 axis expands RORγt+ Tregs to protect from glomerulonephritis |
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| 500 | |a Date Revised 22.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Kidney Int. 2023 Jul;104(1):28-31. - PMID 37349057 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies | ||
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| 650 | 4 | |a Treg-directed therapy | |
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| 700 | 1 | |a Niehus, Christoph B |e verfasserin |4 aut | |
| 700 | 1 | |a Ramcke, Torben |e verfasserin |4 aut | |
| 700 | 1 | |a Hagenstein, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Ehnold, Laura-Isabell |e verfasserin |4 aut | |
| 700 | 1 | |a Nosko, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Warkotsch, Matthias T |e verfasserin |4 aut | |
| 700 | 1 | |a Feindt, Frederic C |e verfasserin |4 aut | |
| 700 | 1 | |a Melderis, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Paust, Hans-Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Sivayoganathan, Varshi |e verfasserin |4 aut | |
| 700 | 1 | |a Jauch-Speer, Saskia-Larissa |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Milagros N |e verfasserin |4 aut | |
| 700 | 1 | |a Indenbirken, Daniela |e verfasserin |4 aut | |
| 700 | 1 | |a Krebs, Christian F |e verfasserin |4 aut | |
| 700 | 1 | |a Huber, Tobias B |e verfasserin |4 aut | |
| 700 | 1 | |a Panzer, Ulf |e verfasserin |4 aut | |
| 700 | 1 | |a Puelles, Victor G |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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