CD4⁺ T Cells Occupy Perivascular and Perifollicular Niches in Healthy Human Skin

Regulatory T cells (Tregs) are specialised T lymphocytes that sit at the nexus of immune regulation and tissue repair. While it is appreciated that a substantial number of Tregs are present in healthy human skin, less is known about their microanatomic spatial localisation. Knowledge about the specialised niches that Tregs occupy may aid in rational drug development to treat dermatologic diseases. Thus, we performed multiplexed immunohistochemistry for CD4 and FOXP3 (the lineage-defining transcription factor of Tregs) on healthy skin sections obtained from eight different cutaneous sites, and quantified Tregs and Tcon in distinct regions. We found that Tregs (CD4⁺ FOXP3⁺) comprised roughly 20% of CD4⁺ T cells in skin and that Tregs and T-conventional cells (Tcon; CD4⁺ Foxp3^-) are enriched in follicularly dense skin and show preferential accumulation in perivascular and perifollicular niches in the upper dermis. Additionally, male skin shows a significant increase in the numbers of Tregs and Tcon, while female skin shows a higher Tcon:Treg ratio. We also find that the frequency of skin Tregs declines over time. Overall, we conclude that the upper dermal perivascular region is a niche that supports the accumulation of CD4⁺ T cells in steady-state human skin.