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

<bold>Background: </bold>Elicitation of allergic contact dermatitis (ACD), an inflammatory type 4 hypersensitivity disease, induces skin infiltration by polyclonal effector CD8 alpha beta T cells and precursors of tissue-resident memory T (T-RM) cells. Because T-RM have long-term potential to contribute to body-surface immunoprotection and immunopathology, their local regulation needs a fuller understanding.<bold>Objective: </bold>We sought to investigate how T-RM-cell maturation might be influenced by innate-like T cells pre-existing within many epithelia.<bold>Methods: </bold>This study examined CD8(+) T-RM-cell maturation following hapten-induced ACD in wild-type mice and in strains harboring altered compartments of dendritic intraepidermal gamma delta T cells (DETCs), a prototypic tissue-intrinsic, innate-like T-cell compartment that reportedly regulates ACD, but by no elucidated mechanism.<bold>Results: </bold>In addition to eliciting CD8 T-RM, ACD induced DETC activation and an intimate coregulatory association of the 2 cell types. This depended on DETC sensing IFN-gamma produced by CD8 cells and involved programmed death-ligand 1 (PD-L1). Thus, in mice lacking DETC or lacking IFN-gamma receptor solely on gamma delta 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-gamma-regulated PD-L1 expression was a trait of human skin-homing and intraepithelial gamma delta T cells.<bold>Conclusions: </bold>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-gamma 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 gamma delta T-cell-deficient settings.