Persistence of mature dendritic cells, Th2A and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4R-alpha blockade

Therapeutic options for autoimmune diseases typically consist of broad and targeted immunosuppressive agents. However, a sustained clinical benefit is rarely achieved, as the disease phenotype usually returns after cessation of treatment. To better understand this kind of 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 included LAMP3+ CCL22+ mature dendritic cells, CRTH2+ CD161+ T helper (“Th2A”) cells, and CRTAM+ cytotoxic T-cells, which expressed high levels of CCL17 (dendritic cells) and IL13 (T-cells). Th2A cells showed a unique cytokine receptor constellation of IL17RB, IL1RL1 (ST2) and CRLF2 expression, suggesting that these are key responders to the AD-typical epidermal alarmins IL-25, IL-33 and TSLP, respectively. We thus identified characteristic immune cell populations in resolved AD indicative of a persisting disease memory, facilitating a rapid response system of epidermal-dermal crosstalk between keratinocytes, dendritic cells and Tcells. This observation may explain the disease recurrence upon termination of immunosuppressive treatments in AD, and it identifies cell types that may be targeted to achieve a more sustained therapeutic response. Comparison of skin cells from patients without and with short-term (16 weeks) or long-term (1 year) treatment with the IL-4Rα blocker dupilumab >>>Raw data are unvailable due to patient privacy concerns<<<