As the only dendritic cells resident in the epidermis, Langerhans cells (LCs) play a critical role in skin immunity. Through their stimulation of donor T cells, LCs likely play a key role in skin graft-versus-host-disease (GVHD), a serious complication that limits the use of allogeneic bone marrow (BM) transplantation. Despite their importance, little is known about the life cycle of LCs, their precursor cells in the blood and their homeostasis after allogeneic BM transplantation. Furthermore, the mechanisms by which LCs influence GVHD have not been elucidated. We have recently established that LCs are maintained by a radio-resistant precursor that self-renew in quiescent skin throughout life. In contrast, LCs are replaced by circulating precursors after major skin injury such as exposure to UV light or donor allo-reactive T cells infiltration. In addition we have recently characterized the circulating LC precursor that repopulate LCs in UV injured skin. We hypothesize that this unique cycle of LC homeostasis;controls skin allogeneic immune responses after transplantation. To address our hypothesis, we will employ complementary approaches using adoptive transfer of hematopoietic precursors in mice and a clinically relevant model for allogeneic hematopoietic stem cell transplantation. Aim 1, will characterize the direct circulating precursor that repopulate skin resident LCs after allo-BMT. Aim 2, will characterize the mechanisms leading to the replacement of host LCs by donor LCs after allog-BMT. Aim 3 Will explore the immunological mechanisms that lead to the protective effect of LC chimerism on skin GVHD. These studies should provide valuable insights into LC regulation of skin immune responses and may lead to improved prevention or treatment of skin GVHD, a major medical problem in transplantation therapy of patients with malignancies.