| Autor: |
Herrnstadt, Georg R., Niehus, Christoph B., Ramcke, Torben, Hagenstein, Julia, Ehnold, Laura-Isabell, Nosko, Anna, Warkotsch, Matthias T., Feindt, Frederic C., Melderis, Simon, Paust, Hans-Joachim, Sivayoganathan, Varshi, Jauch-Speer, Saskia-Larissa, Wong, Milagros N., Indenbirken, Daniela, Krebs, Christian F., Huber, Tobias B., Panzer, Ulf, Puelles, Victor G., Kluger, Malte A., Steinmetz, Oliver M. |
| Zdroj: |
Kidney International; 20230101, Issue: Preprints |
| Abstrakt: |
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. |
| Databáze: |
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