Warp Speed Ahead! Technology-Driven Breakthroughs in Skin Immunity and Inflammatory Disease

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, and genomic and computational technologies have illuminated the complexity of the cutaneous immune cells and their functions in maintaining skin health and driving diseases. 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.

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Under pressure: Stem cell-niche interactions coordinate tissue adaptation to inflammation

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.

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Deciphering the regulatory landscape of fetal and adult γδ T-cell development at single-cell resolution

Sagar et al. DOI: 10.15252/embj.2019104159

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.

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Unraveling Immune-Epithelial Interactions in Skin Homeostasis and Injury.

Mansfield and Naik, Unraveling Immune-Epithelial Interactions in Skin Homeostasis and Injury, Yale J Biol Med 2020 Mar 27;93(1):133-143.

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.

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Choreographing Immunity in the Skin Epithelial Barrier.

The skin interfaces with the external environment and is home to a myriad of immune cells that patrol the barrier to ward off harmful agents and aid in tissue repair. The formation of the cutaneous immune arsenal begins before birth and evolves throughout our lifetime, incorporating exogenous cues from microbes and inflammatory encounters, to achieve optimal fitness and function. Here, we discuss the context-specific signals that drive productive immune responses in the skin epithelium, highlighting key modulators of these reactions, including hair follicles, neurons, and commensal microbes. We thus also discuss the causal and mechanistic underpinning of inflammatory skin diseases that have been revealed in recent years. Finally, we discuss the non-canonical functions of cutaneous immune cells including their burgeoning role in epithelial regeneration and repair. The rapidly growing field of cutaneous immunity is revealing immune mechanisms and functions that can be harnessed to boost skin health and treat disease.

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