The occurrence of graft-versus-host disease (GVHD) in the skin of patients receiving bone-marrow transplants is a common and serious complication, hindering the widespread use of this procedure. Although donor T cells are known to have an active role in GVHD, it is unclear which cells are important in triggering the disease-causing (alloreactive) T-cell response. Now, a study in Nature Medicine by Miriam Merad and colleagues reveals that host Langerhans cells that persist in the skin following bone-marrow transplantation are responsible for the induction of GVHD.

To study the role of Langerhans cells — the main population of antigen-presenting cells in the skin — in GVHD, lethally irradiated mice were transplanted with allogeneic bone marrow and the fate of Langerhans cells assessed. When T cells were depleted from the bone-marrow transplant, host Langerhans cells persisted in the skin, even though the blood and spleen were repopulated with donor-derived dendritic cells. By contrast, when T cells were included in the transplant, host Langerhans cells were replaced by donor-derived cells. The authors show that this occurred by two donor-T-cell-mediated processes: FAS ligand (CD95L)-mediated depletion of host Langerhans cells and the induction of expression of inflammatory chemokines in the skin, which recruit donor Langerhans-cell precursors.

However, mice that received whole bone marrow still developed GVHD, because the depletion of host Langerhans cells occurred after donor T cells cause disease. So, the authors developed a strategy to eliminate host Langerhans cells before donor T-cell infusion. First, irradiated mice were reconstituted with T-cell-depleted bone marrow, allowing complete chimerism to be established in the blood but not the skin. These mice were then exposed to ultraviolet light, which caused host Langerhans cells to migrate out of the skin and allowed repopulation with donor-derived cells. After several weeks, the mice were then retransplanted with bone marrow containing T cells. No GVHD developed in these mice, indicating that Langerhans-cell replacement in the skin is required to prevent GVHD following transplantation of T cells.

Future experiments will address whether exposing patients to ultraviolet light before transplantation might help prevent GVHD in human recipients.