TY - JOUR

T1 - CD4+ T cells inhibit the generation of CD8+ epidermal-resident memory T cells directed against clinically relevant contact allergens

AU - Funch, Anders Boutrup

AU - Weber, Julie Friis

AU - Lohmann, Rebecca Kitt Davidson

AU - Mraz, Veronika

AU - Yeung, Kelvin

AU - Jee, Mia Hamilton

AU - Ødum, Niels

AU - Woetmann, Anders

AU - Johansen, Jeanne Duus

AU - Geisler, Carsten

AU - Menné Bonefeld, Charlotte

N1 - Publisher Copyright: © 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.

PY - 2023

Y1 - 2023

N2 - Background: CD8+ epidermal-resident memory T (TRM) cells play central roles in local flare-up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. Methods: The immune response to cinnamal, ρ-phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well-established mouse model for allergic contact dermatitis that includes formation of TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. Results: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen-dependent. However, the magnitude of the flare-up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM cells, the flare-up response and the epidermal infiltration of neutrophils for all allergens. Conclusion: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8+ TRM cells that recruit neutrophils following re-exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti-inflammatory CD4+ T cells.

AB - Background: CD8+ epidermal-resident memory T (TRM) cells play central roles in local flare-up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. Methods: The immune response to cinnamal, ρ-phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well-established mouse model for allergic contact dermatitis that includes formation of TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. Results: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen-dependent. However, the magnitude of the flare-up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM cells, the flare-up response and the epidermal infiltration of neutrophils for all allergens. Conclusion: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8+ TRM cells that recruit neutrophils following re-exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti-inflammatory CD4+ T cells.

KW - allergic contact dermatitis

KW - CXCL2

KW - epidermal-resident memory T cells

KW - neutrophils

U2 - 10.1111/cod.14316

DO - 10.1111/cod.14316

M3 - Journal article

C2 - 36999574

AN - SCOPUS:85152073074

VL - 88

SP - 425

EP - 437

JO - Contact Dermatitis

JF - Contact Dermatitis

SN - 0105-1873

IS - 6

ER -