Quietly hiding: PD-L1 checkpoint expression in melanocyte stem cell quiescence and aging

Cellular quiescence is a reversible and tightly regulated stem cell function that is essential for healthy aging. However, the control elements of tissue-specific renewal, quiescence, and aging remain poorly understood. Using melanocyte stem cells (McSCs) to model and test the regulation of tissue-specific quiescence, we find that stem cell quiescence is neither a singular nor static process. McSCs display remarkable heterogeneity, with a fraction expressing the immune checkpoint protein PD-L1. Differential gene expression profiling identifies tissue-specific control of this immune privilege, specifically during melanocyte stem cell dormancy. In vitro quiescence assays confirm that inducing quiescence is sufficient to drive PD-L1 expression in melanoblasts and PD-L1 subsequently regulates aspects of melanoblast cell cycling. In vivo, a portion of McSCs appear to leverage this immune checkpoint as a key aspect of their dynamics during the dormant stage of the hair cycle. With age, this dynamic becomes unbalanced, tipping towards a higher proportion of PD-L1-expressing McSCs and a more deeply quiescent McSC pool. Collectively, these findings demonstrate that immune checkpoint expression is a physiological attribute of McSC quiescence and offer PD-L1-expressing quiescent stem cells as molecular targets for potential reactivation in regenerative and gerontological medicine.