Persistence of mature dendritic cells, T _H 2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4Rα blockade

Abstract

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 <i>LAMP3</i> ⁺ <i>CCL22⁺</i> mature dendritic cells, <i>CRTH2</i> ⁺ <i>CD161</i> ⁺ T helper ("T_H2A") cells, and <i>CRTAM</i> ⁺ cytotoxic T cells, which expressed high levels of <i>CCL17</i> (dendritic cells) and <i>IL13</i> (T cells). T_H2A cells showed a characteristic cytokine receptor constellation with <i>IL17RB</i>, <i>IL1RL1</i> (ST2), and <i>CRLF2</i> 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.