Imiquimod 유발 건선양 피부염 모델에서 면역조절 T 세포의 역할

Psoriasis is a common immune-mediated, chronic inflammatory skin disease characterized by widespread erythematous plaque with typical silvery white scale. Among various immune cells, T cells play a pivotal role in development of these characteristic skin changes. In psoriasis, dysregulation of the regulatory T (Treg) cell compartment has been reported. In human psoriasis, defects in the function of Treg cells, as well as a resistance of effector T cells to Treg cell-mediated suppression could contribute to failed T cell regulation. From this background, I hypothesized modulation of Treg cells function can be a feasible therapeutic strategy for the control of chronic inflammation of psoriasis. This study aims to observe the phenotype of Treg cells in imiquimod (IMQ)-induced animal model for psoriasis and to elucidate the functional role of Treg cells using Treg-depletion mice model. Firstly, repetitive application of IMQ on the shaved back skin and one side of ear of mice successfully induced psoriasiform dermatitis model. Interestingly, splenic CD4+Foxp3+ Treg cells were significantly increased in active group, and their expression of markers related with suppressive function, PD-1, CTLA-4, and GITR, are increased on Treg cells in active group. However, prolonged application of IMQ more than one week did not exacerbate IMQ-induced skin inflammation and did not changed splenic and lymph node Treg cells and their suppressive markers. To understand the direct role of Treg cells in IMQ-induced mice model, Treg cell depletion model using Foxp3-DTR-eGFP mice was adopted. Unexpectedly, the transient Treg depletion before the induction of skin inflammation did not worsen IMQ-induced inflammatory change. Moreover, the main source of IL-17 in this mice model, and IL-17-producing γδ T cells were not changed after Treg cell depletion before the induction of skin inflammation. Contrary to early response, transient Treg cell depletion before the starting of late period, skin inflammation was exacerbated. Then, to compare relative importance of IL-17 and Treg depletion, transient Treg-depleted mice were treated with anti-IL-17A monoclonal antibody. The treatment with anti-IL-17A monoclonal antibody partially rescued mice from the exacerbation of disease associated with Treg cell depletion. Taken together, these findings show that Tregs are important for the controlling of on-going inflammation in IMQ-induced skin inflammation. And transient Treg cell depletion acts, at least partly, through increasing IL-17 producing γδ T cells and inflammatory cytokines such as IFN-γ. These results suggest possibility that Treg cells therapy may be of benefit in psoriasis as a supportive therapeutics to current anti-psoriatic treatments based on anti-IL-17 strategies. Further investigations to reveal the detailed dynamic change of Treg cells and their functional phenotypes on different time points in IMQ-induced skin change will be needed for the comprehensive understanding of psoriasis.open박