TY - JOUR
T1 - IFN-γ-dependent interactions between tissue-intrinsic γδ T cells and tissue-infiltrating CD8 T cells limit allergic contact dermatitis
AU - Muñoz-Ruiz, Miguel
AU - Llorian, Miriam
AU - D'Antuono, Rocco
AU - Pavlova, Anna
AU - Mavrigiannaki, Anna Maria
AU - McKenzie, Duncan
AU - García-Cassani, Bethania
AU - Iannitto, Maria Luisa
AU - Wu, Yin
AU - Dart, Robin
AU - Davies, Daniel
AU - Jamal-Hanjani, Mariam
AU - Jandke, Anett
AU - Ushakov, Dmitry S
AU - Hayday, Adrian C
N1 - Funding Information:
Supported by the Francis Crick Institute , which receives core funding from Cancer Research UK (CRUK); the UK Medical Research Council; the Wellcome Trust (FC001003); the CRUK King’s Cancer Centre; the National Institute for Health and Care research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London; and the European Molecular Biology Organization (ALTF 198–2018 to M.M.R.). Y.W. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (220589/Z/20/Z). M.L.I. and D.D. were supported in part by Gamma Delta Therapeutics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
Supported by the Francis Crick Institute, which receives core funding from Cancer Research UK (CRUK); the UK Medical Research Council; the Wellcome Trust (FC001003); the CRUK King's Cancer Centre; the National Institute for Health and Care research Biomedical Research Center at Guy's and St Thomas’ National Health Service Foundation Trust and King's College London; and the European Molecular Biology Organization (ALTF 198–2018 to M.M.R.). Y.W. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (220589/Z/20/Z). M.L.I. and D.D. were supported in part by Gamma Delta Therapeutics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Disclosure of potential conflict of interest: A.C. Hayday is cofounder and equity holder in ImmunoQure AG; receives research support from Takeda Pharmaceuticals, the Wellcome Trust, the Medical Research Council, and Cancer Research UK; and is a consultant for Takeda Pharmaceuticals, Prokarium, ImmunoQure, and TransImmune AG. Y.W. consults for PersonGen BioTherapeutics Ltd. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2023
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85172268436&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2023.07.015
DO - 10.1016/j.jaci.2023.07.015
M3 - Article
C2 - 37562754
SN - 0091-6749
VL - 152
SP - 1520
EP - 1540
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -
