Heterogeneous generation and expansion of epidermal-resident memory T cells in individuals allergic to nickel

BACKGROUND: Nickel is the most frequent cause of allergic contact dermatitis (ACD). Recent studies have shown that epidermal skin-resident memory T (TRM) cells play a central role in ACD. However, how TRM cells accumulate and differentiate in the epidermis of individuals allergic to nickel repeatedly exposed to the metal is not known. OBJECTIVES: To investigate how repeated exposure to nickel affects the clinical reaction and the accumulation and differentiation of epidermal TRM cells in individuals allergic to nickel. METHODS: Twelve participants with nickel allergy were patch-tested three times with nickel, with a 21-day interval between each test, by applying the patch to the same skin site each time. Two days after each patch test, the skin reactions were assessed and clinically scored. Twenty-one days after each patch test, skin biopsies were taken and analysed by flow cytometry and single-cell RNA sequencing. RESULTS: The number of CD4+ and CD8+ T cells in the epidermis and the clinical score increased with each exposure to nickel. Altogether, 90-95% of the T cells were CD69+ TRM cells. We found expanded T helper (Th)2 and/or Th17-like CD4+ and cytotoxic CD8+ TRM cell clones in all individuals; however, CD4+ TRM cells dominated in some participants, whereas CD8+ TRM cell dominated in others. We could not correlate specific T-cell subtypes to the severity of the clinical response. As a common feature, all participants exhibited a polyclonal regulatory T-cell (Treg) population and exhausted-like populations of CD4+ and CD8+ TRM cells and Treg cells in the epidermis. CONCLUSIONS: We determined the complexity of epidermal T cells in individuals allergic to nickel repeatedly exposed to the metal, identifying several distinct clusters of effector and exhausted-like CD4+ and CD8+ TRM and Treg cells. An author video to accompany this article is available online.