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

Abstract

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, <i>in vivo</i> and <i>in vitro</i>, 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 <i>in vitro</i> 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.