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

Abstract

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.

• Authors: Julia Hagenstein, Simon Melderis, Anna Nosko, Matthias T Warkotsch, Johannes V Richter, Torben Ramcke, Georg R Herrnstadt, Jürgen Scheller, Isabell Yan, Hans-Willi Mittrücker, Malte A Kluger, Oliver M Steinmetz
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 30 Issue 8 Pg. 1439-1453 (08 2019) ISSN: 1533-3450 [Electronic] United States
• PMID: 31311828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by the American Society of Nephrology.

Chemical References

• FOXP3 protein, human
• Forkhead Transcription Factors
• Il6ra protein, mouse
• Immunosuppressive Agents
• Interleukin-6 Receptor alpha Subunit
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Receptors, Interleukin-6
• Rorc protein, mouse

Topics

• Animals
• Cell Line
• Crosses, Genetic
• Female
• Forkhead Transcription Factors (metabolism)
• Glomerulonephritis (metabolism, pathology)
• Immunosuppressive Agents (therapeutic use)
• Inflammation
• Interleukin-6 Receptor alpha Subunit (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Necrosis
• Nuclear Receptor Subfamily 1, Group F, Member 3 (metabolism)
• Receptors, Interleukin-6 (genetics, metabolism)
• Signal Transduction
• T-Lymphocytes, Regulatory (immunology)
• Th17 Cells (cytology)