Abstract Text: Early life is a critical period for the development of solid organs and the immune system. Regulatory T cells (Tregs) are present in the skin during the first week of life, but their function in the neonatal skin is unknown.
A peak expression of Treg activation markers was observed on postnatal day 9 (P9). Depletion of early Tregs (eTregs) on P6 and P8 caused a 20% reduction in skin pigmentation on P28. By contrast, pigmentation developed normally after depletion of late Tregs (lTregs) on P10 and P12. Pigment-producing melanocyte marker genes, such as Dct, and PPARγ target genes were downregulated only after depletion of eTregs, and not lTregs. A PARγ antagonist, T0070907, in neonatal mice similarly leads to defective skin pigmentation (p=0.0017). Additionally, PPARγ agonist, GW1929, restores skin pigmentation to homeostatic level in Treg-depleted mice. scRNA-seq analysis revealed higher expression of PPARγ target genes in human neonatal melanocyte in comparison to adult melanocytes. Similarly, PPARγ target genes were elevated in healthy adult melanocytes in comparison to melanocytes in lesional skin of human vitiligo patients.
We report a novel finding that P6-P8 represents a window of Treg-PPARγ axis that defines the melanogenic function of melanocytes. Disruption of this axis results in abrogation of homeostatic pigmentation in the skin. This signalling pathway is differentially regulated in human neonatal and adult melanocytes and is disrupted in vitiligo. Our finding suggests that defective Treg function during neonatal stage leads to disruption of the PPARγ pathway, with implications in vitiligo.
