Faculty Bibliography

Sensory neurons have surfaced as key instigators of skin inflammation. In this issue of Cell, Zhang et al. define an anti-inflammatory Langerhans cell (LC)-neuron-mast cell (MC) circuit that underlies skin immune homeostasis. They uncover a role for LCs in maintaining innervation of MrgprD⁺ nonpeptidergic neurons that restrain MC activation via glutamate secretion.

Cellular cartography of human tissues has provided unprecedented insight into health and disease. In a recent issue of Science, Reynolds et al. (2021) use single-cell transcriptomics to define cell states and gene programs in human skin and uncover fetal programs in dermatological diseases that may fuel inflammatory pathology.

The enteric nervous system is surfacing as a key regulator of intestinal immunity and a liaison of host-commensal interactions. In this issue, Yan et al. identify neuronal interleukin-6 as a potent modulator of regulatory T (Treg) cells in the intestine. This neuroimmune dialog is further refined by commensal microbiota, which impact the enteric nervous system and consequently the intestinal Treg cell pool.

The skin's physical barrier is reinforced by an arsenal of immune cells that actively patrol the tissue and respond swiftly to penetrating microbes, noxious agents, and injurious stimuli. When unchecked, these same immune cells drive diseases such as psoriasis, atopic dermatitis, and alopecia. Rapidly-advancing microscopy, animal modeling, genomic, and computational technologies have illuminated the complexity of the cutaneous immune cells and their functions in maintaining skin health and driving disease. Here we discuss the recent technology-driven breakthroughs that have transformed our understanding of skin immunity and highlight burgeoning areas that hold great promise for future discoveries.

Stem and progenitor cells (SCs) are emerging as key drivers of tissue adaptation to inflammation caused by microbes, injury, noxious agents, and other onslaughts. These pressures are most acutely experienced in epithelial tissues such as the skin and gut that interface with the external environment. Thus, here we review how epithelial SCs of the skin and intestine, along with their supportive niches, sense and respond to inflammation for the sake of preserving tissue integrity. We highlight inflammation-induced plasticity in SCs and their progeny and the lasting memory that forms thereafter. The burgeoning area of SC responses to inflammatory stressors may expand therapeutic perspectives in epithelial inflammatory conditions, wound repair, cancers, and aging.

γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high-resolution map of γδ T-cell differentiation from the fetal and adult thymus using single-cell RNA sequencing. We reveal novel sub-types of immature and mature γδ T cells and identify an unpolarized thymic population which is expanded in the blood and lymph nodes. Our detailed comparative analysis reveals remarkable similarities between the gene networks active during fetal and adult γδ T-cell differentiation. By performing a combined single-cell analysis of Sox13, Maf, and Rorc knockout mice, we demonstrate sequential activation of these factors during IL-17-producing γδ T-cell (γδT17) differentiation. These findings substantially expand our understanding of γδ T-cell ontogeny in fetal and adult life. Our experimental and computational strategy provides a blueprint for comparing immune cell differentiation across developmental stages.

The skin serves as a front line of defense against harmful environmental elements and thus is vital for organismal survival. This barrier is comprised of a water-tight epithelial structure reinforced by an arsenal of immune cells. The epithelial and immune components of the skin are interdependent and actively dialogue to maintain health and combat infectious, injurious, and noxious stimuli. Here, we discuss the molecular mediators of this crosstalk that establish tissue homeostasis and their dynamic adaptations to various stress conditions. In particular, we focus on immune-epithelial interactions in homeostatic tissue regeneration, during natural cycling of the hair follicle, and following skin injury. We also highlight the epithelial derived factors that orchestrate immunity. A comprehensive and mechanistic understanding of dynamic interactions between cutaneous immune cells and the epithelium can be leveraged to develop novel therapies to treat of range of skin diseases and boost skin health.