T lymphocytes in human skin play essential roles in immune surveillance and tissue homeostasis, with distinct populations residing in the epidermal and dermal compartments. To characterize the molecular basis of their compartmentalized functional specialization, we performed proteomic analysis of total T cell populations isolated from healthy human skin, combining flow cytometry and liquid chromatography–tandem mass spectrometry. We quantified 5985 proteins across epidermal and dermal T cell populations, identifying 2177 significantly differentially expressed proteins (FDR < 0.05), including 1008 with >2-fold changes. Compared with dermal T cells, epidermal T cells showed elevated intensity of tissueresidency marker CD69, co-stimulatory protein CD27, complement components (C3, C4a, and Factors B and D), and proteins involved in oxidative phosphorylation and cholesterol metabolism. Epidermal T cells also exhibited higher levels of antimicrobial S100 proteins, chemokine receptor CCR6, IL-18, and MHC class I molecules, while, in contrast, dermal T cells showed increased expression of CXCR4, IL-16, and MHC class II-related proteins. While these distinct proteomic signatures suggest compartment-specific adaptations in metabolism, immune surveillance, and antigen presentation, the results should be interpreted as exploratory, given methodological limitations. Nonetheless, this study provides a valuable molecular resource for understanding the specialization of T cells within different skin layers and offers a basis for future investigations into skin immune biology and its potential implications in disease.

Fungal skin infections represent a significant global health burden, affecting approximately one billion people annually. Despite their prevalence and major global health impact, the molecular mechanisms underlying pathogenicity remain largely uncharacterized. Here we present high quality genomic datasets for 51 fungal strains, representing highly prevalent and clinically relevant species associated with human skin infections. Comparative genomics reveal substantial variation in genome size and gene contents, indicating genome compaction occurred as the fungi transitioned from free-living to host-associated lifestyles. We report two non-hybrid strains of Trichosporon ovoides, the causative agent of white piedra. Our analysis reveals substantial differences in metabolic adaptations across skin-associated fungi, corresponding to distinct body-site and nutrient niches. Significant differences were also present in the distribution of virulence factors and adhesins, which are imperative for biofilm formation and antifungal resistance. We discuss metabolic adaptation and virulence mechanisms revealed by our data in the context of clinical presentations, highlighting shared and lineage-specific adaptations. Together, these insights advance our knowledge of skin-associated fungi and their infection mechanisms while providing valuable resources and a foundation for future analyses to improve diagnostics and therapeutics for diverse diseases.

Fungal skin infections represent a significant global health burden, affecting approximately one billion people annually. Despite their prevalence and major global health impact, the molecular mechanisms underlying pathogenicity remain largely uncharacterized. Here we present the genomes of 66 fungal strains, representing highly prevalent and clinically relevant species associated with human skin infections. Using comparative genomics, we investigate whether the taxonomic groups in this collection of skin fungi differ in their genome architecture, metabolic capacity, secreted enzyme repertoires, adhesin content, and predicted virulence determinants. These analyses reveal substantial variation in genome size and gene contents, indicating genome compaction occurred as the fungi transitioned from free-living to host-associated lifestyles. We report two non-hybrid strains of Trichosporon ovoides, the causative agent of white piedra. Our analyses reveal substantial differences in metabolic adaptations across skin-associated fungi, corresponding to body-site and nutrient niches. Significant differences are also observed in the distribution of virulence factors and adhesins, which are imperative for biofilm formation and antifungal resistance. We discuss metabolic adaptation and virulence mechanisms revealed by our data in the context of clinical presentations, highlighting shared and lineage-specific signatures of adaptations. Together, these insights advance our understanding of skin-associated fungi and their mechanisms of infection.