A Novel Role for IL-6 Receptor Classic Signaling: Induction of ROR γ t + Foxp3 + Tregs with Enhanced Suppressive Capacity.

Autor:	Hagenstein J; III. Department of Medicine and., Melderis S; III. Department of Medicine and., Nosko A; III. Department of Medicine and., Warkotsch MT; III. Department of Medicine and., Richter JV; III. Department of Medicine and., Ramcke T; III. Department of Medicine and., Herrnstadt GR; III. Department of Medicine and., Scheller J; Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Dusseldorf, Germany., Yan I; Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and., Mittrücker HW; Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and., Kluger MA; III. Department of Medicine and., Steinmetz OM; III. Department of Medicine and o.steinmetz@uke.de.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2019 Aug; Vol. 30 (8), pp. 1439-1453. Date of Electronic Publication: 2019 Jul 16.
DOI:	10.1681/ASN.2019020118
Abstrakt:	Background: 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. Methods: 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. Results: 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, in vivo and in vitro , 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 in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra -/- Tregs resulted in severe aggravation of GN in mice. Conclusions: 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. (Copyright © 2019 by the American Society of Nephrology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu