Persistence of mature dendritic cells, TH2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4Rα blockade.

The constants of atopic dermatitis recurrence: Atopic dermatitis (AD) is an inflammatory disease characterized by itching and widespread eczema. Moderate to severe AD is commonly treated by IL-4Rα blockade with dupilumab, yet cessation of this antibody therapy leads to disease recurrence, with the long-term immunologic effects of this treatment remaining unclear. Using scRNA-seq and proteomics of skin suction blisters from patients with AD, Bangert et al. characterized the immunologic milieu in AD skin during long-term IL-4Rα blockade. They identified that dendritic cells and T cells maintained an inflammatory phenotype during long-term IL-4Rα blockade, suggesting that these populations might be central to disease recurrence by maintaining a "disease memory." These data and this dataset may contribute to the design of therapies that help prevent AD recurrence. Therapeutic options for autoimmune diseases typically consist of broad and targeted immunosuppressive agents. However, sustained clinical benefit is rarely achieved, as the disease phenotype usually returns after cessation of treatment. To better understand tissue-resident immune memory in human disease, we investigated patients with atopic dermatitis (AD) who underwent short-term or long-term treatment with the IL-4Rα blocker dupilumab. Using multi-omics profiling with single-cell RNA sequencing and multiplex proteomics, we found significant decreases in overall skin immune cell counts and normalization of transcriptomic dysregulation in keratinocytes consistent with clearance of disease. However, we identified specific immune cell populations that persisted for up to a year after clinical remission while being absent from healthy controls. These populations included LAMP3⁺CCL22⁺ mature dendritic cells, CRTH2⁺CD161⁺ T helper ("T_H2A") cells, and CRTAM⁺ cytotoxic T cells, which expressed high levels of CCL17 (dendritic cells) and IL13 (T cells). T_H2A cells showed a characteristic cytokine receptor constellation with IL17RB, IL1RL1 (ST2), and CRLF2 expression, suggesting that these cells are key responders to the AD-typical epidermal alarmins IL-25, IL-33, and TSLP, respectively. We thus identified disease-linked immune cell populations in resolved AD indicative of a persisting disease memory, facilitating a rapid response system of epidermal-dermal cross-talk between keratinocytes, dendritic cells, and T cells. This observation may help to explain the disease recurrence upon termination of immunosuppressive treatments in AD, and it identifies potential disease memory–linked cell types that may be targeted to achieve a more sustained therapeutic response. [ABSTRACT FROM AUTHOR]