Tissue-Resident Memory and Follicular/Peripheral Helper PD-1⁺ T Cells Infiltrate Lesional Skin in Atopic Dermatitis

Atopic dermatitis (AD) is primarily driven by Th2 cells. Although CD3⁺ T cells and CD11c⁺ cells predominate in lesional (L) over nonlesional (NL) skin, both sites harbor epidermal dysregulation and a type 2 profile relative to healthy skin. Therapeutics focusing on Th2-mediated pathways partially fill an unmet medical need, highlighting the importance of further characterizing the adaptive and innate immune landscape in L versus NL skin. Paired L and NL biopsies and matched blood samples were collected from 10 patients. The immunophenotype and cytokine profile of immune cells were examined at the single-cell level using multiparameter flow cytometry and unsupervised analysis. L compared with NL skin was predominantly infiltrated by CD4⁺CD103⁺PD-1⁺ tissue-resident memory T cells (TRMs) that positively correlated with disease severity (EASI). CD4⁺ CD103⁺PD-1⁺ TRMs coexpressed CD25 and ICOS. Frequencies of skin-resident CD4⁺CD103^-PD-1⁺CXCR5⁺CCR5^+/- follicular/peripheral helper T cells (Tfh/Tph) were also augmented in L skin. CCR5^- Tfh/Tph coexpressed ICOS, OX40, and IFN-γ along with IL-4 or CD120b while CCR5⁺ Tfh/Tph coexpressed IL-4Rα. Furthermore, inflammatory monocytes and monocyte-derived dendritic cells (Mo-DCs) positively correlated with CD4⁺CD103⁺PD-1⁺ TRMs and EASI in L skin. These findings enhance our knowledge of AD's innate and adaptive immune profile which may facilitate the discovery of novel therapeutic targets.