Characterisation of NK cells and other cytotoxic killer cells in atopic dermatitis using single cell RNA sequencing

特应性皮炎(AD)患者皮损中多种免疫细胞亚型如T细胞，特别是Th2细胞、巨噬细胞和树突状细胞的聚集对皮肤炎症具有维持作用，而某些细胞类型似乎具有调节功能。最近，在中至重度AD患者中观察到，患者外周血中的自然杀伤(NK)细胞总数显著减少，成熟的CD56dim CD57+NK细胞丢失，皮肤中活化的NK细胞转录信号丰富。此外，在小鼠AD模型中，促进NK细胞的存活和增殖可以减少炎症以及2型固有淋巴样细胞(ILC2)和嗜酸性粒细胞的数量。基于这些观察，人们推测在AD中，NK细胞是否从外周招募到炎症皮肤作为对2型皮肤炎症的内源性反调节反应，然而，它们也可能具有促炎作用。到目前为止，在AD的背景下，还没有深入和纵向的跨组织的NK细胞表型。该项目旨在从单个细胞水平全面界定AD患者皮肤和血液中NK细胞的异质性，检测NK细胞效应分子的功能，并分析抗IL4Rα抗体DUPILUMA和抗IL13抗体Tralokinumab阻断2型AD的效果。

The accumulation of multiple immune cell subtypes such as T cells, in particular Th2 cells, macrophages, and dendritic cells in lesional skin of patients with atopic dermatitis (AD) is known to have a sustaining role for the inflammation of the skin, while some cell types appear to have a regulatory function. Recently, a marked reduction of total peripheral blood natural killer (NK) cells along with a loss of mature CD56dim CD57+ NK cells and an enrichment of activated NK cell transcriptomic signatures in lesional skin has been observed in independent sets of patients with moderate to severe AD. Further, in a murine AD model, promotion of the survival and proliferation of NK cells reduced inflammation as well as the number of type 2 innate lymphoid cells (ILC2) and eosinophils. Based on these observations it has been speculated whether in AD, NK cells are recruited from the periphery to the inflamed skin as an endogenous counterregulatory response to type 2 skin inflammation, however, they could as well have inflammation promoting effects. So far, no in-depth and longitudinal NK cell phenotyping across tissues has been carried out in the context of AD. The proposed project aims at comprehensively defining NK cell heterogeneity at the single-cell level in both skin and blood of patients with AD, to examine NK cell effector functions, and to analyse the effects of type-2 blockade with the anti-IL4Rα antibody dupilumab and the anti-IL13 antibody tralokinumab.