IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T Cells

Abstract

T memory/effector cells (Tmem/eff) isolated from psoriatic patients are chronically activated and poorly suppressed by regulatory T cells (Treg). The proinflammatory cytokine IL-6, which signals through Stat3, allows escape of Tmem/eff cells from Treg-mediated suppression in a murine system. We show here that IL-6 protein is markedly elevated and most highly expressed by CD31+ endothelial cells and CD11c+ dermal dendritic cells (DCs) in lesional psoriatic skin. We hypothesized that exposure to high IL-6 in lesional tissue may lead to the dampened Treg function observed in psoriasis patients. Indeed, we found that IL-6, but not other Stat3-activating cytokines, was necessary and sufficient to reverse human T cell suppression by Treg in an in vitro model using activated DCs as a source of IL-6. IL-6Rα and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6Rα expression on Treg exceeded that of effector T cells, and both populations phosphorylated Stat3 in response to IL-6. Phosphorylation of Stat3 in T cells contributes to Th17 differentiation and we identify cells within lesional tissue that coexpress CD3, IL-17, and IL-6, indicating that Th17 cells are present in vivo within the psoriatic Tmem/eff population and contribute to IL-6-mediated resistance to Treg suppression. Taken together, T lymphocytes trafficking into lesional psoriatic skin encounter high IL-6 from endothelial cells, DCs, and Th17 cells, enabling cutaneous T cell escape from Treg suppression and Th17 participation in inflammation. Targeting IL-6 signaling pathways in psoriasis may rebalance Treg/T effector activity and ameliorate disease.

In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

“…The expression of IL17 is regulated through the activity of STAT3 (27), a transcription factor that is induced by IL6 (28) and has a demonstrated importance in tumor progression, as reviewed elsewhere (29). IL6Rα expression on Treg exceeds that of effector T cells, and both populations respond to IL6 by phosphorylating STAT3 (30). These observations are consistent with the Stat3-dependent expression of IL17 by the Treg.…”

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

“…For instance, in T cells, deletion of Stat3 in various autoimmune disease models was found to increase Foxp3 + Tregs along with a reduction in overall disease progression (21,22,30). Contrary to the unchanged or elevated IFN-γ levels from Stat3 ablation in those studies, our findings indicate that populations of Th1 and CD8 + T cells expressing IFN-γ were both reduced in VAT, whereas Foxp3 + Treg subsets were elevated.…”

LIF in the regulation of T-cell fate and as a potential therapeutic

“…64 Counter-active effects of IL-6 on self-tolerance have been demonstrated in a clinical study of psoriasis 65 where high IL-6 protein expression by CD31 þ endothelial cells and CD11c þ dermal dendritic cells in lesioned psoriatic skin was associated with dampened Treg function. IL-6-R and gp130 were significantly elevated in the psoriatic effector T cells compared with controls.…”