Histone demethylase LSD1 is required for the embryonic development of dendritic epidermal T cells and Langerhans cells

Mouse epidermis contains two important immune cells, dendritic epidermal T cells (DETCs) and Langerhans cells (LCs), which regulate skin immunity and are involved in the pathogenesis of skin diseases. Recent lineage-tracing studies have uncovered that, both adult mouse DETCs and LCs are derived from embryonic yolk-sac-derived hematopoietic precursors, and self-maintain after birth. However, how to regulate their ontogeny and homeostasis remains unclear. Lysine-specific demethylase 1 (LSD1), known to mediate the demethylation of lysine amino acids on histone proteins, plays a key role in the maintenance and differentiation of hematopoietic stem cells. To investigate the role of LSD1 in development and maintenance of DETCs and LCs, we generated two mutant mouse models. The first model was Csf1rCre.LSD1fl/fl conditional knockout (cLSD1KO) mouse in which LSD1 was deficient in macrophage/monocytes and DETCs from embryonic stage. The second model was Ubc-ERcre.LSD1 KO mouse in which LSD1 postnatal deletion was timely-induced by tamoxifen (TAM). In adult cLSD1KO mice, we found that LSD1 constitutive deletion led to a severe loss of DETCs and LCs, suggesting that LSD1 is required for ontogeny and/or homeostasis. Interestingly, adult mice with inducible LSD1 deletion had comparable DETCs and LCs compared to WT mice, indicating that LSD1 is dispensable for their maintenance. Using mouse programmed mating strategy, we found that DETCs were almost completely eliminated from the entire skin at E14.5 or epidermis at E18.5 and P0 of cLSD1KO embryos, while LC precursors were modestly reduced in cLSD1KO newborns. Lack of LSD1 impaired embryonic thymic Vγ3+γδ T cell survival and blocked their maturation. Finally, BM chimera experiments showed that LCs and skin resident macrophages failed to be regenerated from LSD1KO BMs under inflammatory condition. Overall, our data suggest that LSD1 serves as a key epigenetic regulator to control DETCs and LCs development