Type 17 T-cell subset divergence in hidradenitis suppurativa versus psoriasis: a comparative single-cell...

IL-17-producing Type 17 T (T17) cells are central drivers of inflammation in both psoriasis and hidradenitis suppurativa (HS), as evidenced by the clinical efficacy of IL-17-targeting therapies. However, therapeutic responses differ substantially between diseases, raising the possibility that the composition and regulation of T17 states are disease context dependent.

To define disease-specific T17 subset composition and regulatory T-cell (Treg) transcriptional programs in psoriasis and HS at single-cell resolution, and to generate hypothesis framework regarding their potential relationship to differential therapeutic responses.

We performed integrated single-cell RNA sequencing (scRNA-seq) analysis of lesional skin from psoriasis (n=20), HS (n=8), atopic dermatitis (AD; n=4), and healthy controls (n=19). T17 subsets were defined based on IL17A, IL17F, IFNG, and IL10 expression, and FOXP3 expression was used to identify Tregs. Comparative transcriptomic analyses were conducted across diseases to characterize subset composition and functional gene programs.

Psoriasis lesions were enriched in IL17A ⁺ IFNG ⁺ T17 cells exhibiting cytotoxic and tissue-resident memory signatures, whereas this subset was markedly reduced in HS (19.83% vs 1.27%). In contrast, HS lesions showed expansion of IL17A ⁺ IL17F ⁺ and IL17F ⁺ IL10 ^- T17 subsets, with the IL17A ⁺ IL17F ⁺ subset demonstrating enhanced inflammatory (TNF, CSF2, IL21, IL1B, CSF3) and proliferative (MKI67) programs, along with increased IL1R1 and OX40 expression. Tregs in both diseases showed reduced IL10 and immunoregulatory markers; however, HS Tregs uniquely expressed proinflammatory mediators including IL17A, IL17F, CXCL13, IL1B, and CSF3, indicating a more inflammatory transcriptional state. Dual immunohistochemistry identified cells showing nuclear FOXP3 staining together with IL-1β, IL-17A, or IL-17F protein staining in HS lesions.

These findings reveal a marked divergence in type 17 immunity between psoriasis and HS. HS is characterized by expansion of IL17A ⁺ IL17F ⁺ T17 cells with an IL-1-associated inflammatory program and inflammatory remodeling of Tregs, rather than enrichment of IL-23-responsive IL17A ⁺ IFNG ⁺ T17 cells observed in psoriasis. This disease-specific immune architecture provides a hypothesis-generating framework for potentially different responses to pathway-targeted therapies and motivates further evaluation of therapeutic approaches in HS, including dual IL-17A/IL-17F blockade and IL-1-targeted approaches.