Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy

Background: Tissue-resident memory T (Trm) cells are detrimental in patients with numerous chronic inflammatory diseases, including allergic contact dermatitis (ACD). Objectives: 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. Methods: We used an experimental model of ACD (ie, contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8(+) T cells. Results: 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. Conclusion: 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.