Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis

Background: Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Pathologic conversion of regulatory T (Treg) cells into inflammatory cytokine-producing cells is thought to be an important step in the progression of autoimmunity, but whether loss of normal Treg cell function contributes to SSc is unknown. Objective: We sought to determine whether Treg cells in the blood and skin of patients with SSc acquired abnormal production of effector cytokines. Methods: Peripheral blood and skin biopsy specimens were collected from control subjects and patients with limited or diffuse SSc. Flow cytometry was used to evaluate expression of cell-surface proteins and the cytokine production profile of forkhead box protein 3-positive Treg cells compared with forkhead box protein 3-negative conventional T cells. Results: Treg cells in the blood of patients with SSc had a normal phenotype and did not produce T-effector cytokines. In contrast, Treg cells from skin affected by SSc produced significant amounts of IL-4 and IL-13. Although Treg cells in the blood of patients with SSc did not make TH2 cytokines, they contained a significantly higher proportion of skin-homing cells expressing TH2 cell-associated chemokine receptors. Evidence that IL-33 caused the differentiation of skin Treg cells into TH2-like cells, combined with high tissue-localized expression of this cytokine in patients with SSc and expression of the ST2 chain of the IL-33 receptor on skin-localized Treg cells, suggests that IL-33 might be an important stimulator of tissue-localized loss of normal Treg cell function. Conclusion: These data are the first evidence for the presence of TH2-likeTreg cells in human autoimmunity and show that Treg cell plasticity can be tissue specific. Localized dysfunction of Treg cells is a previously unknown factor that might contribute to fibrosis in patients with SSc.