Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment...

Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes and T cells were examined in the same lesions of patients before and during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A blocker) treatment. Among CD11c⁺HLA-DR⁺ mononuclear phagocytes, CD64^brightCD163^-CD14^brightCD1c^-CD1a^‒ inflammatory monocyte‒like cells were the predominant IL-23-producing cells and, together with CD64^-CD163^-CD14^-IL-23p19^-TNF-α⁺ inflammatory dendritic cell‒like cells, were increased in lesional compared with those in nonlesional skin taken from the same patient. Within T cells, CD8⁺CD49a⁺ and/or CD103⁺ tissue-resident memory T cells, CD4⁺CD25⁺FoxP3⁺ regulatory T cells, and CD4⁺CD49a^-CD103^- T cells were increased. Moreover, CD4⁺CD49a^-CD103^- T cells and the relatively rare CD8⁺ memory T cells equally contributed to IL-17A production. Both treatments decreased the frequencies of inflammatory monocyte‒like, inflammatory dendritic cell‒like, and CD4⁺CD49a^-CD103^- T cells. In contrast, guselkumab reduced memory T cells while maintaining regulatory T cells and vice versa for secukinumab. Neither drug modified the frequencies of IL-17A⁺IL^‒17F⁺/^- CD4⁺ or CD8⁺ T cells. This study reveals the identity of the major IL-23⁺ mononuclear phagocyte and IL-17⁺ T-cell subsets in psoriatic skin lesions and paves the way for a better understanding of the mode of action of drugs targeting the IL-23/IL-17A pathway in psoriasis.