IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN.
| Autor: | Diefenhardt P; III. Medizinische Klinik., Nosko A; III. Medizinische Klinik., Kluger MA; III. Medizinische Klinik., Richter JV; III. Medizinische Klinik., Wegscheid C; Institut für Experimentelle Immunologie und Hepatologie, and., Kobayashi Y; Department of Immunobiology and The Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut., Tiegs G; Institut für Experimentelle Immunologie und Hepatologie, and., Huber S; Department of Immunobiology and The Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut.; I. Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany; and., Flavell RA; Department of Immunobiology and The Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut., Stahl RAK; III. Medizinische Klinik., Steinmetz OM; III. Medizinische Klinik, o.steinmetz@uke.de. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2018 Jul; Vol. 29 (7), pp. 1825-1837. Date of Electronic Publication: 2018 Jun 04. |
| DOI: | 10.1681/ASN.2017091044 |
| Abstrakt: | 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. (Copyright © 2018 by the American Society of Nephrology.) |
| Databáze: | MEDLINE |
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