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

Publication date: Available online 15 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Pia Gamradt, Léo Laoubi, Audrey Nosbaum, Virginie Mutez, Vanina Lenief, Sophie Grande, Daniel Redoulès, Anne-Marie Schmitt, Jean-François Nicolas, Marc Vocanson

Abstract

Background

Tissue-resident memory T cells (Trm) are detrimental in numerous chronic inflammatory diseases, including allergic contact dermatitis (ACD).

Objectives

To analyze the contribution of Trm 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, i.e. contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB) which is mediated by CD8+T cells.

Results

Our data show that early effector T cells accumulated in the skin during the acute CHS reaction and gave rise to epidermal CD8+ Trm expressing a specific set of immune checkpoint receptors (ICR), such as PD-1 and Tim-3. Those Trm remained in the epidermis for several weeks and mediated the eczema exacerbations, which developed upon allergen re-exposure without the contribution of circulating specific T cells. Furthermore, allergen-induced Trm reactivation was constrained, since 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 as well as the sustained expression of ICR.

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 in situ via their ICR should open new perspectives for the treatment of ACD.

Graphical abstract

http://bit.ly/2CqTY4z