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

Abstract

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 (TRM) cells. Because TRM have long-term potential to contribute to body-surface immunoprotection and immunopathology, their local regulation needs a fuller understanding. OBJECTIVE: To investigate how TRM cell maturation might be influenced by innate-like T cells pre-existing within many epithelia. METHODS: We examined CD8+ TRM maturation following hapten-induced ACD in wild type mice and in strains harbouring altered compartments of dendritic intraepidermal γδ T cells (DETC), a prototypic tissue-intrinsic, innate-like T cell compartment that reportedly regulates ACD, but with no elucidated mechanism. RESULTS: In addition to eliciting CD8 TRM, ACD induced DETC activation and an intimate co-regulatory association of the two cell types. This depended on DETC sensing IFNγ produced by CD8 cells and involved PD-L1. Thus, in mice lacking DETC or lacking IFNγR 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 IFNγ-regulated PD-L1 expression was a trait of human skin-homing and intraepithelial γδ T cells. CONCLUSION: The size and quality of the tissue-infiltrating CD8 T cell response during ACD can be profoundly regulated by local T cells responding to IFNγ and involving PD-L1. Thus, inter-individual 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.