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 early as postnatal day 3 (P3) where they localize to hair follicle (HF) structures and enter a dynamic flux of activation marker expression. Punctual ETreg depletion from P6-P8, but not later, results in defective HF melanocyte SC (MeSC) mediated skin pigmentation in juvenile life. Transcriptomic analysis of the whole skin on P9 exhibited immediate and pronounced changes in MeSC markers and perturbation of Peroxisome proliferator-activated receptor-γ (PPARγ) target genes in the HF. Accordingly, punctual ETreg depletion combined with short-term PPARγ agonization restored skin pigmentation. Single cell profiling of P9 skin revealed that PPARγsignalling 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 exhibited a 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. One Sentence Summary: PPARγ pathway functions downstream of neonatal Tregs to regulate melanocyte stem cell function.