Establishment of an Immune-Cell Niche in Skin

Michael Rosenblum, MD, PhD

Professor of Dermatology, School of Medicine, and Vice-Chair of Research, UCSF Department of Dermatology

December 2023

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Dr. Rosenblum presented his research that identified a novel immune cell niche and its possible clinical applications.

First, Dr. Rosenblum discussed regulatory T cells (Tregs) and their role in skin disease. Autoimmune and inflammatory diseases result from disruption in the balance of autoreactive and regulatory cells. Tregs are a type of regulatory cell in the skin that play a critical role in controlling inflammation. Dr. Rosenblum’s research showed that skin Tregs are involved in follicle cycling, epidermal barrier repair, and regulating fibroblast interactions and fibrosis.

Second, Dr. Rosenblum presented studies leading to the characterization of T helper 2 (Th2) interacting fascial fibroblasts (TIFFs) in mice. The research began by identifying a wave of Tregs that entered the skin shortly after birth. A mouse model developed to investigate the role of this Treg wave showed that transient neonatal Treg depletion caused hyperplasia of unknown stromal cells that led to the formation of fibrous bands in the subcutis. These fibrous bands appeared to normalize over time after Tregs repopulated. However, when neonatally Treg-depleted mice were subsequently Treg-depleted as adults, the fibrous bands recurred. Thus, although the skin histology appeared to return to normal after neonatal Treg depletion, memory of the perturbation remained. Further analysis of the unknown stromal cells showed high levels of Interleukin-33 (IL-33) expression.

Investigation into the immune composition of neonatal Treg-depleted mouse skin showed an increase in Th2 cells localized in the subcutis and expressed high levels of the IL-33 receptor. The unknown stromal cells were linked to Th2 accumulation and renamed TIFFs. Subsequent studies demonstrated that TIFFs create a niche that activates and maintains Th2 cells in the subcutis and increases disease susceptibility later in life. Human skin stroma showed TIFF-like cell clusters.

Finally, Dr. Rosenblum described the clinical translation of this research to eosinophilic fasciitis (EF) and atopic dermatitis (AD). EF is a rare condition characterized by fascial inflammation and skin tightening. The skin of people with EF has similar histological features to that of mice with neonatal Treg depletion, including the fibrous band structures. Analysis of skin donated by an EF patient showed inflamed fascia composed of TIFFs driven to expand by Th2 cells.

In patients with AD, TIFFs are increased in lesional and non-lesional skin. Dr. Rosenblum hypothesizes that TIFFs play a role in the establishment and maintenance of Th2 cells in the skin of these patients.