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

Significance Statement The pleiotropic cytokine IL-6 has commonly been regarded as the master switch of inflammation because it augments proinflammatory T helper 17 cell (Th17) responses and suppresses anti-inflammatory regulatory T cells (Tregs). This study challenges this paradigm. Studies in mice show that IL-6 receptor classic signaling effectively induces Th17 responses but also, in contrast to the previous concept, increases Treg activation. Engagement of the IL-6 receptor results in the generation of a unique ROR γ t-expressing Treg subtype with enhanced suppressive capacity. Expansion of this highly activated, IL-6–dependent effector Treg population is associated with a significantly improved outcome of experimental acute GN. These results shed new light on IL-6 biology and help to establish IL-6 directed therapies for GN. 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.