Resident T cells are implicated in the maintenance and recurrence of psoriatic lesions. Whether skin that has not yet experienced psoriasis in patients with established disease harbors pathogenic T cells is less investigated.

We sought to analyze the composition of resident T cells and T cell–driven tissue responses in skin never affected by psoriasis from patients with mild disease.

Never-lesional skin from patients with psoriasis (NLP) was collected from those with mild disease. T-cell profiles were assessed by using confocal imaging and flow cytometry. Tissue responses to T-cell stimulation were measured by using multiplex and NanoString technology.

T-cell activation ex vivo triggered psoriasiform and type I interferon tissue responses in NLP psoriasis. Accordingly, keratinocytes from NLP responded to IFN-γ stimulation with myxovirus 1 (MX1) expression and IFN-α release. Additionally, CCR6-expressing resident T cells poised to produce IFN-γ and IL-17 were enriched in epidermis from NLP, whereas dermal tissue responses and T-cell compositions were similar to those in healthy skin. Finally, keratinocytes from NLP exposed to IL-17 and skin explants exposed to common fungal antigens responded with upregulation of the CCR6 ligand CCL20.

Epidermal resident T cells capable of triggering psoriasiform tissue responses accumulate in epidermis from NLP. Our global analysis of NLP reveals that microbial interplay with genetically predisposed keratinocytes might shape the local pool of resident T cells.