CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; INSERM, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR 5308, Lyon, France.
Allergology & Clinical Immunology, CH Lyon-Sud, Pierre-Benite, France.
J Allergy Clin Immunol. 2019 Jun;143(6):2147-2157.e9. doi: 10.1016/j.jaci.2018.11.048. Epub 2019 Jan 15.
Tissue-resident memory T (Trm) cells are detrimental in patients with numerous chronic inflammatory diseases, including allergic contact dermatitis (ACD).
We sought to analyze the contribution of Trm cells to the chronicity and severity of ACD and to define the local parameters regulating their development and functions.
We used an experimental model of ACD (ie, contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8 T cells.
Our data show that early effector T cells accumulated in the skin during the acute contact hypersensitivity reaction and gave rise to epidermal CD8 Trm cells expressing a specific set of inhibitory checkpoint receptors (ICRs), such as programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain 3 (TIM-3). Those Trm cells remained in the epidermis for several weeks and mediated the eczema exacerbations, which developed on allergen re-exposure without the contribution of circulating specific T cells. Furthermore, allergen-induced Trm cell reactivation was constrained because treatment with ICR antagonists dramatically enhanced the magnitude and severity of eczema exacerbations. Finally, we show that the persistence of the allergen in the epidermis for long periods of time was responsible for both the development and maintenance of epidermal Trm cells, as well as the sustained expression of ICRs.
Although CD8 Trm cells are key for the pathophysiology of ACD, intrinsic mechanisms control their reactivation to prevent damaging immunopathology. Developing strategies targeting the reactivation of skin Trm cells in situ through their ICRs should open new perspectives for the treatment of ACD.
组织驻留记忆 T（Trm）细胞在许多慢性炎症性疾病患者中是有害的，包括过敏性接触性皮炎（ACD）。
我们旨在分析 Trm 细胞对 ACD 的慢性和严重性的贡献，并确定调节其发育和功能的局部参数。
我们使用了一种 ACD 的实验模型（即对 2,4-二硝基氟苯的接触超敏反应），该模型由 CD8 T 细胞介导。
我们的数据表明，早期效应 T 细胞在急性接触超敏反应期间在皮肤中积累，并产生表达特定抑制检查点受体（ICR）的表皮 CD8 Trm 细胞，如程序性细胞死亡蛋白 1（PD-1）和 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM-3）。这些 Trm 细胞在表皮中停留数周，并介导了在过敏原再次暴露时发生的湿疹加重，而无需循环特异性 T 细胞的贡献。此外，ICR 拮抗剂的治疗极大地增强了湿疹加重的程度和严重性，从而限制了过敏原诱导的 Trm 细胞再激活。最后，我们表明，过敏原在表皮中的长时间存在是表皮 Trm 细胞的发展和维持以及 ICR 的持续表达的原因。
尽管 CD8 Trm 细胞是 ACD 病理生理学的关键，但内在机制控制着它们的再激活以防止破坏性的免疫病理学。通过它们的 ICR 靶向体内皮肤 Trm 细胞的再激活的策略应该为 ACD 的治疗开辟新的前景。
