Langerhans cells (LCs) are the resident immune cells of the epidermis, forming a critical component of the skin immune barrier. Despite sharing a developmental origin with tissue-resident macrophages, LCs adopt a functional identity closely resembling that of dendritic cells (DCs). What drives this unique DC-like identity in LCs but not other tissue macrophages remains poorly understood.
A key barrier to addressing this question is the biology of LCs themselves: seeded in the skin before birth, LCs persist throughout life as a self-renewing population, making it difficult to dissect the signals that govern their identity. To overcome this, we have exploited the clinical phenomenon of graft-versus-host disease (GVHD), in which host LCs are eliminated by donor T cells following bone marrow transplantation and subsequently replaced by bone marrow-derived monocytes. This provides a unique and clinically relevant window into LC differentiation.
Using this model, we have investigated how LC identity is programmed within the skin microenvironment, and specifically what signals allow macrophage precursors to acquire a DC-like identity to repair the LC network in adulthood. These findings shed light on the mechanisms that instruct tissue-specific immune identity, with broader implications for our understanding of skin immunity and macrophage/DC biology.