043 Pellino-1 promotes intrinsic activation of skin-resident IL-17A-producing T cells in psoriasis

Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. How the activation of skin-resident T17 cells is regulated in the psoriasis niche has been poorly understood yet. We performed single-cell RNA-sequencing of relapsing and resolving psoriatic lesions in the same patient, which revealed distinct T cell subsets in relapsing psoriasis exhibiting highly enriched gene signatures for (1) tissue-resident T cells, (2) T17 cells, and (3) NF-kB signaling pathway including PELI1. Pellino-1 (Peli1) belongs to a member of E3 ubiquitin ligase mediating immune receptor signaling cascades including NF-kB pathway. Peli1-deficient mice were profoundly protected from psoriasiform dermatitis with reduced IL-17A production and NF-kB activation in γδT17 cells. Mice with conditional depletion of Peli1 treated with FTY720 revealed that Peli1 was intrinsically required for the activation of skin-resident T17 cells. Notably, pharmacological inhibition of Peli1 significantly ameliorated murine psoriasiform dermatitis and IL-17A production from ex vivo human skin explants modeling psoriasis. Thus, our results highlight that targeting Peli1 would be a promising therapeutic strategy for psoriasis by limiting skin-resident T17 cell immune responses.