026 The impaired suppressive activity and altered response to IL-33 of regulatory T cells in a psoriasis model may be due to decreased ST2 expression

Abstract

Interleukin 33 (IL-33), initially described as an alarmin, is released by cells following cell damage. It fulfills numerous functions in infections and inflammatory diseases by modulating both the innate and the adaptive immune system. IL-33, however, can also act in an immunosuppressive fashion by inducing regulatory T cells (Treg). Enhanced IL-33 levels are found both in the skin and the serum of psoriatic patients. On the other hand, in psoriasis Treg appear to be impaired in their suppressive function. To study whether “psoriatic” Treg are impaired in their response to IL-33, we utilized the imiquimod (IMQ)-induced psoriasis like model. IL-33 expression was elevated in both skin and serum of IMQ-treated mice, as demonstrated by in situ immunofluorescence staining and ELISA. However, the suppressive activity of Treg obtained from IMQ-mice was reduced as indicated by adoptive transfer experiments. To study whether the response of Treg to IL-33 is altered in IMQ-mice, Treg from untreated or IMQ-mice were incubated with IL-33 and injected into naïve mice which were sensitized thereafter. The suppressive capacity of Treg obtained from untreated mice could be further enhanced by IL-33, whereas Treg from IMQ-mice did not respond to IL-33. IL-33 exerts its activity via binding to its receptor ST2. ST2 expression identifies a highly activated, strongly suppressive Treg subset, which is superior to ST2− Treg in suppressing CD4+ T cell proliferation. FACS analysis of Foxp3 +CD4+CD25+ cells revealed that ST2 expression on IMQ-Treg was down-regulated in comparison to Treg from untreated animals. Decreased expression of the IL-33 receptor could be an explanation for the weaker response of Treg to IL-33 in IMQ-treated mice and their reduced suppressive activity. Further studies have to elucidate the mechanism by which ST2 expression is down-regulated in the IMQ-model and whether reduced ST2 expression can be also observed in psoriasis.