Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Retired, Gurnee, IL, USA.
Sci Rep. 2019 Nov 27;9(1):17675. doi: 10.1038/s41598-019-53240-z.
Foxp3 regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4Foxp3RORγtIL-17A cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4Foxp3RORγtIL-17A cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.
Foxp3+ 调节性 T 细胞 (Tregs) 是皮肤固有 T 细胞的主要组成部分。尽管 Tregs 通常具有保护作用，但已证明它们在包括银屑病在内的人类疾病中会产生促炎细胞因子。Treg 领域的一个重大障碍是鉴定或开发用于研究这种 Treg 可塑性的模型系统。为了克服这一差距，我们在 IL-23 介导的银屑病样皮炎的小鼠模型中分析了皮肤固有 Tregs。我们的结果表明，IL-23 驱动了 Tregs 的积累；包括一个表达 RORγt 并产生 IL-17A 的亚群。这种群体的产生被 RORγt 反向激动剂化合物和临床相关治疗药物所减弱。在体外，IL-23 从 Treg 细胞中驱动 CD4Foxp3RORγtIL-17A 细胞的生成。总之，我们的数据表明，IL-23 通过诱导一群 CD4Foxp3RORγtIL-17A 细胞来驱动 Treg 可塑性，这些细胞可能在疾病发病机制中发挥作用。通过这项工作，我们定义了一个体外系统和一个临床前体内小鼠模型，可用于进一步研究银屑病背景下的 Treg 稳态和可塑性。
