Early life regulatory T cells modulate PPARγ-dependent skin pigmentation

Abstract

AbstractIn the adult mouse skin, regulatory T cells (Tregs) control stem cell activation. However, whether Tregs are similarly important during stem cell-driven events, such as postnatal development, is unknown. Here, we reveal that during a transient period of postnatal development, neonatal Tregs are critical for PPARγ signalling in the skin, which is in turn necessary for the function of melanocyte stem cells, which produce skin pigmentation. Flow cytometry and immunofluorescence reveal Tregs in neonatal skin by postnatal day 3. These Tregs localise near hair follicles, and express 1.5-8-fold higher levels of activation markers CD25, CD27, CTLA4 and ICOS than their counterparts in the lymph node. Depletion of Tregs on postnatal day 6 (P6) and P8 disrupted skin pigmentation on P28. Transcriptomic analysis of the whole skin on P9 revealed immediate decreases in melanocyte stem cell markers and perturbation of PPARγ target genes in the hair follicles upon Treg depletion. In support of this observation, PPARγ antagonist T0070907 hinders pigmentationin vivo, while PPARγ agonist, GW1929, restores pigmentation in Treg-depleted mice. Therefore, Tregs sustain PPARγ signalling activity to regulate skin pigmentation. Finally, scRNA-seq analysis of vitiligo patients’ skin reveals diminished PPARγ target genes in lesional keratinocytes. Similarly, scRNA-seq of Treg-sufficient and Treg-depleted mouse skin on day 9 uncovers reduced PPARγ pathway activity in HF keratinocytes. Overall, neonatal Tregs are key to sustaining skin PPARγ signaling, which is vital for melanocyte stem cell function and pigmentation.One Sentence SummaryPPARγ pathway functions downstream of neonatal Tregs to regulate melanocyte stem cell function.