Early skin seeding regulatory T cells modulate PPARγ-dependent skin pigmentation.

The maintenance of adult tissue homeostasis is dependent on the functional cross-talk between stem cells (SCs) and tissue-resident immune cells. This reciprocal relationship is also essential for tissue organogenesis during early life. The skin harbors a relatively large population of regulatory T cells (Tregs) that accumulate within the first two weeks after birth. A functional role for early skin seeding Tregs (ETregs) during the first week of life is currently unexplored. Here, we show that skin Tregs are detected as early as postnatal day 3 (P3) and enter a dynamic flux of activation marker expression. Punctual ETreg depletion from P6-P8, but not later, resulted in defective hair follicle (HF) melanocyte SC (MeSC) mediated skin pigmentation in juvenile life. Transcriptomic analysis of the whole skin on P9 indicated immediate and pronounced changes in MeSC markers, as well as perturbation of PPARγ target genes in the HF. Accordingly, punctual ETreg depletion, combined with short-term PPARγ antagonization, restored skin pigmentation. Single-cell profiling of P9 skin revealed that PPARγ signalling activity is preferentially diminished in the HF epithelium upon loss of ETregs. Finally, we explored changes in the single-cell transcriptome of the human tissue disorder, vitiligo, characterized by a lack of melanin and consequent skin depigmentation. These analyses showed that the HF cells from lesional vitiligo skin exhibit significant downregulation in PPARγ pathway activation, relative to heathy controls. Overall, ETregs in neonatal skin are critical for sustaining HF PPARγ signaling, which is vital for facilitating MeSC mediated skin pigmentation during postnatal development.