The suppressive activity of regulatory T cells (Treg) in the absence of the G-protein coupled receptor 109a (HCA2, Puma) is significantly reduced as demonstrated in the contact hypersensitivity model. Here we asked whether the same phenomenon can be observed in other skin inflammatory models. To address this issue, we used the psoriasis like imiquimod (IMQ)-induced skin inflammation model in mice. Application of IMQ on the skin of HCA2- knock out (KO) or wild type (WT) animals resulted in psoriasiform skin (skin thickening, erythema, scales). The inflammatory response was significantly stronger in HCA2-KO animals. Histopathological analysis revealed that IMQ induced acanthosis, hyperkeratosis and an inflammatory infiltrate which were more pronounced in HCA2-KO. The same applied for splenomegaly induced by IMQ. Flow cytometry of Foxp3+ cells obtained from lymph nodes and spleens of IMQ-treated animals revealed significantly upregulated expression of IL-6 in HCA2-KO in comparison to WT mice. To study whether the reduced immunosuppressive activity of Treg is responsible for the enhancement of inflammation, Treg cells obtained from WT or HCA2-KO mice were injected into IMQ-treated WT animals. In contrast to WT Treg, HCA2-KO Treg did not suppress the inflammatory effect of IMQ, but even enhanced the disease pattern. Since IL-6 suppresses the development of Treg we next studied whether IL-6 is responsible for the observed proinflammatory effect. Treg were isolated from KO or KO treated with a monoclonal anti-IL-6-antibody. The inflammatory response was significantly mitigated in the recipients of Treg obtained from anti-IL6-treated HCA2-KO mice compared to recipients of Treg from untreated HCA-KO donors. Histopathological analysis revealed reduced inflammatory and epidermal effects in the skin of recipients of cells obtained from anti-IL-6-treated HCA2-KO donors, suggesting that the overexpression of IL-6 in HCA2-KO mice might be responsible for the functional failure of Treg.

ESDR201 - Decreased efficacy of regulatory T cells in the absence of HCA2 is due to overexpression of IL-6

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING