At the 2025 Inflammatory Skin Disease Summit, Michael Rosenblum, MD, PhD, professor of dermatology at UCSF, presented an in-depth account of more than a decade of work examining regulatory T cells (Tregs) and their interactions with stromal populations in the skin. He opened by reflecting on how the field has evolved, noting that “I used to have several slides that introduced these cells, and now with the Nobel Prize… I think everyone knows about T regs.” His talk moved from developmental immunology to stromal cell biology and ultimately to early translational insights in human disease.1

Rosenblum emphasized that peripheral tissues, not lymphoid organs, house the majority of Tregs. As he explained, “the skin and GI tract actually has overwhelmingly the majority of Tregs in the body,” a distribution suggesting that their functions extend well beyond immunosuppression. Over the past 15 years, his laboratory has demonstrated that Tregs in the skin are deeply integrated into physiologic processes. They facilitate hair follicle cycling, promote epithelial repair, regulate fibroblast activation and fibrosis, and protect hair follicle stem cells from immune-mediated injury. Collectively, these findings position cutaneous Tregs as critical components of tissue maintenance rather than merely modulators of inflammation.

A major focus of the presentation was the discovery of what Rosenblum’s group calls the neonatal “Treg wave.” In mice, Tregs flood into the skin between postnatal days 6 and 13, rising “from about 20% of the CD4 compartment to over 80%.” This developmental surge coincides with the emergence of hair follicles, first environmental exposures, and rapid structural maturation of the skin. The team hypothesized that proper establishment of this Treg wave is essential for immune imprinting, an early-life event that may determine susceptibility to inflammatory conditions later in life.2

To test this, MSTP student Ian Boothby used Foxp3-DTR mice to selectively deplete Tregs during this neonatal window. Although the mice appeared clinically normal, histology told a different story. Boothby observed the emergence of an unusual fibroblast population forming fibrotic strands within the subcutaneous fat, accompanied by panniculitis and a stable Th2-rich immune environment. These fibroblasts, initially termed TIFFs (Th2-interacting fascial fibroblasts), seemed to establish a self-supporting niche with Th2 cells. The concept that short-term neonatal perturbation of Tregs could reprogram stromal and immune architecture well into adulthood raised questions regarding early-life determinants of skin disease.

The group then sought to characterize these fibroblasts more precisely. Single-cell RNA sequencing of CD45-negative stromal cells revealed a distinct cluster defined by high expression of the IL-13 receptor α1 subunit and other markers. Translating transcriptomic signatures into surface phenotypes, the researchers identified the cells as CD26^high CD29⁺ fibroblasts positioned along the fascial plane. Their transcriptional profile strongly overlapped with a fibroblast population described by Shannon Turley’s group at Genentech, known as PI16-positive universal fibroblasts, suggesting that Rosenblum’s TIFFs were part of a widely conserved stromal lineage.

To support mechanistic studies, the laboratory generated an inducible PI16-CreERT2 mouse, allowing lineage tracing, targeted ablation, or conditional gene deletion within this fibroblast subset. Rosenblum joked that “once you have a hammer… the whole world then becomes a nail,” underscoring how foundational this tool has become for ongoing experiments.

Postdoctoral fellow Max Kinay used this system to investigate the role of PI16-positive fibroblasts in bleomycin-induced skin fibrosis. Surprisingly, deletion of these fibroblasts did not reduce fibrosis; instead, it intensified dermal collagen deposition. Rosenblum noted, “It was the exact opposite result,” a finding they validated repeatedly. These fibroblasts therefore appear to act as regulatory fibroblasts that suppress, rather than promote, pathological scarring. Work is ongoing to identify the molecular pathways through which these cells restrain fibrosis.

Another postdoctoral fellow, Hitoshi Terui, examined whether PI16-positive fibroblasts contribute to abscess formation. By infecting reporter mice with Staphylococcus aureus, he observed that these fibroblasts rapidly encircled bacterial foci, creating the fibrotic wall around an abscess. When the fibroblasts were deleted, abscesses enlarged and bacteria disseminated to systemic organs such as the spleen and kidney. These observations suggest that PI16-positive fibroblasts are essential for confining pathogens and preventing systemic spread.

Rosenblum then addressed the translational implications of this work. Using cross-species integrated analysis, his team mapped the mouse TIFF/PI16 transcriptional signature onto human single-cell datasets and found a clearly identifiable counterpart in normal human skin. Initial patient studies focused on eosinophilic fasciitis (EF) because its pathology—bands of fibrosis within subcutaneous fat and a type 2 immune infiltrate—resembled their neonatal Treg-depletion model. In an untreated patient with EF, PI16-like fibroblasts were expanded, and Th2 cells localized to the same fascial regions, supporting the hypothesis that a fibroblast–Th2 axis may contribute to disease. Recruitment of additional patients with EF, morphea, and other fibrotic conditions is underway.

In closing, Rosenblum proposed a unifying terminology. “I propose that we call these cells… PI16-expressing fibroblasts, or PIFs,” a name that captures both their molecular identity and broad functional relevance. His presentation underscored a paradigm shift: fibroblasts are not passive structural elements but active regulators of immune tone, fibrosis, and microbial containment. For clinicians, these findings point toward an emerging fibroblast–immune axis that could shape future therapeutic strategies for inflammatory and fibrotic skin diseases.

References

Rosenblum M. Regulating skin inflammation. Oral presentation. Presented at: Inflammatory Skin Disease Summit 2025; November 12-15, 2025; New York, New York.Scharschmidt TC, Vasquez KS, Truong HA, et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity. 2015;43(5):1011-1021. doi:10.1016/j.immuni.2015.10.016