IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells

WA Goodman, AD Levine, JV Massari… - The Journal of …, 2009 - journals.aai.org
WA Goodman, AD Levine, JV Massari, H Sugiyama, TS McCormick, KD Cooper
The Journal of Immunology, 2009journals.aai.org
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 …
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.
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