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Hagenstein, Julia; Melderis, Simon; Nosko, Anna; Warkotsch, Matthias T; Richter, Johannes V; Ramcke, Torben; Herrnstadt, Georg R; Scheller, Jürgen; Yan, Isabell; Mittrücker, Hans-Willi; Kluger, Malte A; Steinmetz, Oliver M
Journal of the American Society of Nephrology, 08/2019, Volume: 30, Issue: 8Journal Article
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. 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. 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, and , 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 suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra Tregs resulted in severe aggravation of GN in mice. 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.
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