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 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 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.

A Literature Review of Real-World Effectiveness and Safety of Dupilumab for Atopic Dermatitis

“…Likewise, withdrawal of dupilumab at an early phase is not recommended. Recently, Bangert et al revealed specific immune cell populations, mature dendritic cells, TH2A, and Tc2 cells, that persisted for up to one year after clinical amelioration obtained by dupilumab while being absent from healthy controls J o u r n a l P r e -p r o o f (Bangert et al, 2021). Their data suggest that it takes more than one year for treatment with dupilumab to bring immunological remission even after having achieved clinical amelioration.…”

“…Likewise, withdrawal of dupilumab at an early phase is not recommended. Recently, Bangert et al. (2021) revealed specific immune cell populations, mature dendritic cells, TH2A, and Tc2 cells, that persisted for up to 1 year after clinical amelioration obtained by dupilumab while being absent from healthy controls.…”

Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance

“…Function of DCs is controlled mainly by stimuli and environmental context, and we can harness this to induce activating or tolerogenic immune responses (17). Therefore, when DCs are targeted with vaccines for either immunity or tolerance, it may be important to filter out beneficial subsets, but it is equally important to provide the right combination of triggers for DCs in order to shape a T cell activating or tolerizing phenotype (43)(44)(45).…”

Regulation of Tissue Immune Responses by Local Glucocorticoids at Epithelial Barriers and Their Impact on Interorgan Crosstalk

“…On the contrary, the study further confirms the insensitivity of T H 2 cells towards GCs in allergic sensitization and inflammation ( 65 ). Especially the persistence of a T H 2 subset, which displays an inflammatory memory phenotype in non-lesioned AD skin, was suggested to play a major role in the recurrence of AD conditions in patients treated with the monoclonal anti-IL-4Rα antibody dupilumab ( 66 ).…”