IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN

J Am Soc Nephrol. 2018 Jul;29(7):1825-1837. doi: 10.1681/ASN.2017091044. Epub 2018 Jun 4.

Abstract

Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum-induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.Results Compared with controls, mice with IL-10Ra-/- Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra-/- Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra-/- Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra-/- T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.

Keywords: IL-10R; IL-17; Interleukin 10; Treg; cytokines; glomerulonephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cytokines / metabolism
  • Dendritic Cells / physiology
  • Disease Models, Animal
  • Down-Regulation
  • Glomerulonephritis / immunology*
  • Interleukin-10 / metabolism*
  • Interleukin-10 Receptor alpha Subunit / genetics
  • Interleukin-10 Receptor alpha Subunit / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Nephritis / immunology
  • Nephritis / metabolism*
  • Receptors, CCR6 / metabolism
  • Signal Transduction*
  • T-Lymphocytes, Regulatory / metabolism*
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism

Substances

  • CCR6 protein, mouse
  • Cytokines
  • IL10 protein, mouse
  • Interleukin-10 Receptor alpha Subunit
  • Receptors, CCR6
  • Interleukin-10