The interplay between epidermal barrier distribution, microbiota composition, and immune infiltrate defines and stratifies psoriasis patients and is associated with disease severity.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by keratinocyte hyperproliferation, primarily driven by the IL-23/IL-17 axis. In addition to immune response, various skin components, including the epidermal barrier and the skin microbiota, have been individually implicated in the disease pathogenesis. Here, we aimed to investigate the interplay between epidermal tight junctions, Staphylococcus aureus enterotoxin B (SEB), and CD4 T cell-mediated immune responses. By immunofluorescence analyses of skin biopsies, we observed that claudin-1 distribution was significantly altered in psoriatic patients, which correlated with the localization of and SEB across skin layers and with disease severity. Furthermore, functional CD4 TCRvβ17 cells were associated with SEB presence in patients skin and positively correlated with psoriasis severity. Notably, in patients with SEB detected in the dermis, CD4 TCRvβ17 IL-17 cells were linked to barrier abnormalities. Unsupervised analysis stratified psoriasis patients into three groups based on SEB presence and location, supporting the previous findings. The patient group with SEB in the dermis exhibited improved responses to biological therapy, including reductions in PASI score, claudin-1 fragmentation, and SEB presence, and CD4 TCRvβ17 cell percentages. Our findings emphasize the complex interplay between epidermal barrier distribution, SEB localization, and functional CD4 TCRvβ17 cells in psoriatic skin, highlighting their potential in patient stratification in association with the severity of the disease.