IFN-γ-dependent interactions between tissue-intrinsic γδ T cells and tissue-infiltrating CD8 T cells limit allergic contact dermatitis

Miguel Muñoz-Ruiz, Miriam Llorian, Rocco D'Antuono, Anna Pavlova, Anna Maria Mavrigiannaki, Duncan McKenzie, Bethania García-Cassani, Maria Luisa Iannitto, Yin Wu, Robin Dart, Daniel Davies, Mariam Jamal-Hanjani, Anett Jandke, Dmitry S Ushakov, Adrian C Hayday

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Elicitation of allergic contact dermatitis (ACD), an inflammatory type 4 hypersensitivity disease, induces skin infiltration by polyclonal effector CD8 αβ T cells and precursors of tissue-resident memory T (TRM) cells. Because TRM have long-term potential to contribute to body-surface immunoprotection and immunopathology, their local regulation needs a fuller understanding.

OBJECTIVE: We sought to investigate how TRM-cell maturation might be influenced by innate-like T cells pre-existing within many epithelia.

METHODS: This study examined CD8+ TRM-cell maturation following hapten-induced ACD in wild-type mice and in strains harboring altered compartments of dendritic intraepidermal γδ T cells (DETCs), a prototypic tissue-intrinsic, innate-like T-cell compartment that reportedly regulates ACD, but by no elucidated mechanism.

RESULTS: In addition to eliciting CD8 TRM, ACD induced DETC activation and an intimate coregulatory association of the 2 cell types. This depended on DETC sensing IFN-γ produced by CD8 cells and involved programmed death-ligand 1 (PD-L1). Thus, in mice lacking DETC or lacking IFN-γ receptor solely on γδ cells, ACD-elicited CD8 T cells showed enhanced proliferative and effector potentials and reduced motility, collectively associated with exaggerated ACD pathology. Comparable dysregulation was elicited by PD-L1 blockade in vitro, and IFN-γ-regulated PD-L1 expression was a trait of human skin-homing and intraepithelial γδ T cells.

CONCLUSIONS: The size and quality of the tissue-infiltrating CD8 T-cell response during ACD can be profoundly regulated by local innate-like T cells responding to IFN-γ and involving PD-L1. Thus, interindividual and tissue-specific variations in tissue-intrinsic lymphocytes may influence responses to allergens and other challenges and may underpin inflammatory pathologies such as those repeatedly observed in γδ T-cell-deficient settings.

Original languageEnglish
Pages (from-to)1520-1540
Number of pages21
JournalJournal of Allergy and Clinical Immunology
Issue number6
Early online date8 Aug 2023
Publication statusPublished - Dec 2023

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