The spatial and single-cell landscape of skin: Charting the multiscale regulation of skin immune function

Immune regulation is a key function of the skin, a barrier tissue that exhibits spatial compartmentalization of innate and adaptive immune cells. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have facilitated systems-based investigations into the molecular and cellular features of skin immunity at single-cell resolution, identifying cell types that maintain homeostasis in a coordinated manner, and those that exhibit dysfunctional cell-cell interactions in disease. Here, we review how technological innovation is uncovering the multiple scales of heterogeneity in the immune landscape of the skin. The microanatomic scale encompasses the skin’s diverse cellular components and multicellular spatial organization, which govern the functional cell interactions and behaviors necessary to protect the host. On the macroanatomic scale, understanding heterogeneity in cutaneous tissue architecture across anatomical sites promises to unearth additional functional immune variation and resulting disease consequences. We focus on how single-cell and spatial dissection of the immune system in experimental models and in humans has led to a deeper understanding of how each cell type in the skin contributes to overall immune function in a context-dependent manner. Finally, we highlight translational opportunities for adopting these technologies, and insights gleaned from them, into the clinic.