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

Abstract

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 1 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 1 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

Analysis of Skin-Resident Memory T Cells Following Drug Hypersensitivity Reactions

“…Previous case reports have noted an absence of circulating drug-reactive T cells in severe T cellmediated cutaneous reactions (Iriki et al, 2014), raising the possibility that skin-resident T RM cells are key mediators of such skin hypersensitivity reactions. Moreover, recent work has shown that a reduction in T RM cell function after immune checkpoint blockade therapy may reduce the severity of the nondrug hypersensitivity disease allergic contact dermatitis (Gamradt et al, 2019). Here, our findings show that the skin T cells persist and convert to the T RM cell phenotype following intradermal drug challenge, supporting the hypothesis that skin T RM cells may contribute to cutaneous drug hypersensitivity.…”

Enhancing the efficacy of immunotherapy using radiotherapy

“…A recent study in a mouse model revealed that PD-1 and TIM-3 blockade worsened skin inflammation caused by T RM . 108 The interaction of T RM with radiotherapy alone is less well-understood, and most studies combined radiotherapy with other therapies. In a preclinical study of cervical cancer, the combination of a cancer vaccine (HPV E6/E7) with local X-ray radiation increased the number of intratumoral CD103 + CD8 + T cells and was also associated with increased treatment efficacy.…”

Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

“…In recent years, contact allergy has been used to explore how Toll‐like receptors, the inflammasome and endogenous danger signals impact on the hapten specific CD8 + T‐cell response and skin inflammation . Most recently, Gamradt et al discovered that intrinsic control mechanisms such as immune regulatory (PD‐1 and TIM‐3) signalling determine whether the cytotoxic CD8 + T cells will be reactivated and hence prevent tissue injury. Blocking of immune checkpoints in vivo leads to severe contact hypersensitivity responses with low hapten doses.…”