医学
20立方厘米
C-C趋化因子受体6型
肾小球肾炎
免疫学
肾
内科学
免疫系统
趋化因子
趋化因子受体
作者
Georg R. Herrnstadt,Christoph B. Niehus,Torben Ramcke,Julia Hagenstein,Laura-Isabell Ehnold,Anna Nosko,Matthias T. Warkotsch,Frederic C. Feindt,Simon Melderis,Hans‐Joachim Paust,Varshi Sivayoganathan,Saskia-Larissa Jauch-Speer,Milagros N. Wong,Daniela Indenbirken,Christian F. Krebs,Tobias B. Huber,Ulf Panzer,Victor G. Puelles,Malte A. Kluger,Oliver M. Steinmetz
标识
DOI:10.1016/j.kint.2023.02.027
摘要
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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