Faculty Bibliography

Our body's most outward facing epithelial barrier, the skin, serves as the frontline defense against myriad environmental assailants. To combat these motley threats, the skin has evolved a sophisticated immunological arsenal. In this article, I provide an overview of the skin's complex architecture and the distinct microniches in which immune cells reside and function. I review burgeoning literature on the synchronized immune, stromal, epithelial, and neuronal cell responses in healthy and inflamed skin. Next, I delve into the distinct requirement and mechanisms of long-term immune surveillance and tissue adaptation at the cutaneous frontier. Finally, by discussing the contributions of immune cells in maintaining and restoring tissue integrity, I underscore the constellation of noncanonical functions undertaken by the skin immune system. Just as our skin's immune system benefits from embracing diverse defense strategies, so, too, must we in the immunology research community support disparate perspectives and people from all walks of life.

Aberrant epidermal differentiation is a hallmark of inflammatory skin diseases, including psoriasis and atopic dermatitis. If and how differentiated epidermal cells contribute to inflammatory pathology is unclear. In their new article in the Journal of Investigative Dermatology, Shao et al. (2021) report that IRAK2 signaling downstream of IL-1 and IL-36 links epidermal differentiation and skin inflammation.

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.