Atopic dermatitis remission and recurrence are preceded by changes in ex-tissue-resident memory T cell abundance

While targeted therapeutics have transformed the treatment of inflammatory skin disorders, symptoms typically return upon drug withdrawal, reflecting the relapsing remitting trajectory of these conditions. The role of tissue-resident memory T (Trm) cells in recurrence is well established, but the contribution of other memory populations is poorly understood. To address this question, we investigated the immune changes underlying drug-induced remission and recurrence in atopic dermatitis (AD). We used single-cell multi-omics to profile serial blood samples (∼1.3M cells; 5 timepoints over 24 weeks) and skin biopsies (spatial transcriptomics at baseline and week 12) from patients receiving an IL4Rα inhibitor. We found that drug-induced AD remission was preceded by an expansion of memory regulatory T cells in blood and skin. These shifts were accompanied by a rapid decrease in the abundance of blood CD103+/CD4+ ex-Trm cells recirculating from skin. Notably, the reduced frequency of ex-Trm cells was apparent after 3 days of treatment, well in advance of clinical remission. The analysis of independent patient cohorts confirmed this and showed that the decline in ex-Trm cell abundance was reversed upon disease recurrence. Thus, we uncovered early shifts in circulating memory T cells, which anticipate the resolution and return of skin inflammation in AD.